Newborns who had low concentrations of vitamin D in blood spot samples had an increased risk of developing multiple sclerosis (MS) as adults, according to a new study published online on November 30 in Neurology.

Growing research evidence supports an association between low vitamin D levels and an increased risk of MS, and studies have shown that vitamin D dietary supplementation confers an MS-protective effect. Additionally, patients with MS who live in the Northern hemisphere seem slightly more likely to have been born in April or May, suggesting that low exposure to vitamin D in utero during low-sunlight months may increase MS risk.

The results of the current study, which corroborate previous findings, "provide a rationale for universal vitamin D supplementation in pregnancy," the study authors, led by Nete Munk Nielsen, MD, MSc, PhD, researcher in epidemiology at the Statens Serum Institut in Copenhagen, Denmark, wrote.

For the study, researchers identified 521 adult patients with MS and 972 age- and sex-matched controls in Denmark who as babies had provided dried blood spot samples to the Danish Newborn Screening Biobank. The researchers used liquid chromatography tandem mass spectroscopy to measure levels of 25-hydroxyvitamin D (25[OH]D) in these samples.

They found that lower levels of 25[OH]D in neonates' blood samples were associated with an increased risk of developing MS. After dividing the neonates' vitamin D levels into quintiles, the researchers found that the risk of developing MS as an adult was highest among patients who had the lowest concentrations of vitamin D as newborns (<20.7 nmol/L), and lowest among patients with the highest concentrations of vitamin D (≥48.9 nmol/L).

Overall, treating blood vitamin D concentrations as a continuous variable, the researchers calculated that every 25 nmol/L increase in 25[OH]D resulted in a 30 percent reduced risk of developing MS. The results remained consistent after the researchers adjusted for parental ethnicity, birthweight, and gestational age in a multivariable analysis.

The results, the study authors say, support two sets of findings: that vitamin D plays a protective role in the development of MS, and that vitamin D levels in utero affect the risk of developing MS as an adult. The mechanism of this effect is not yet understood, but animal studies suggest it may relate to the effect of vitamin D deficiency in altering mitochondrial, cytoskeletal, and synaptic brain functions, the study authors noted.

Since vitamin D deficiency among pregnant women is highly prevalent globally, the researchers concluded, vitamin D supplementation should be strongly considered during pregnancy to potentially protect both mother and newborn.

The researchers noted several limitations to their study. Among them, 25[OH]D stored in the Biobank may have degraded due to storage conditions and levels of 25[OH]D measured in neonatal blood may be different from 25[OH]D levels in utero.

US veterans with epilepsy who were deployed in the Iraq and Afghanistan conflicts were twice as likely to die between 2011 and 2015 as veterans without epilepsy, according to an analysis of Veterans Health Administration (VA) data in the November 11 Morbidity and Mortality Weekly Report published by the Centers for Disease Control and Prevention.

Seizure disorders like epilepsy have been associated with traumatic brain injuries sustained during active duty, the study authors noted. In addition, people who have epilepsy are generally more likely to die than people without epilepsy, partly because of the high number of associated comorbidities. But they said the study is the first to identify a specific link between epilepsy and mortality for US veterans of the Iraq and Afghanistan conflicts.

The findings suggest that clinicians should seek out evidence-based interventions to help manage epilepsy and related comorbidities, the study authors wrote.

Led by Mary Jo Pugh, PhD, associate professor of epidemiology and biostatistics at the University of Texas Health Science Center at San Antonio, the researchers assessed data on US veterans who received VA care in 2010 and 2011. To ensure they were active VA users, all veterans included in the study cohort had at least one inpatient or outpatient visit in both years. Using diagnostic codes and records of prescriptions for antiseizure drugs, the researchers identified 2,187 veterans with epilepsy; the remaining 318,396 were considered not to have epilepsy. Then they used VA vital status files to determine the occurrence and date of death.

The researchers used the VA's vital status records to identify five-year mortality (2011-2015). They found that between January 2011 and December 2015, nearly five times more veterans with epilepsy from the Afghanistan and Iraqi conflicts (4.6 percent) had died by the end of the follow-up period compared to those without epilepsy (1 percent), comprising a 2.6 times higher risk of mortality. The results remained consistent after controlling for demographic characteristics and other comorbidities associated with death (adjusted hazard ratio = 2.6; CI = 2.1-3.2).

Additionally, the vets in the epilepsy cohort were more likely to have other comorbidities, including post-traumatic stress disorder, depression, substance abuse disorder, suicidality, hypertension, and traumatic brain injury.

Health care providers should ensure that veterans with epilepsy are receiving appropriate care and filling their prescriptions for antiseizure medications, the study authors wrote. Additionally, public health agencies like the VA should implement evidence-based self-management programs for those with chronic diseases. Such programs, they wrote, should study the participants' long-term outcomes and support linkages with community health care and social service providers.

The researchers noted several limitations to the findings; among them, the study excluded veterans who were not treated in VA facilities during the study period, which limits the generalizability of the results; epilepsy care received outside of the VA was not accounted for; and some of the veterans may have been misdiagnosed with epilepsy after a psychogenic nonepileptic seizure.

People in late middle age who had migraine with aura had a significantly increased risk of cardioembolic stroke over the course of 20 years, according to a new study published online on November 9 in Neurology.

The researchers examined the association in three stroke subtypes, including thrombotic, cardioembolic, and lacunar strokes, but the association was only significant in cardioembolic stroke. Migraneurs without visual aura did not have a significant risk for cardioembolic stroke.

"The results suggest that visual aura symptoms may be related to distal emboli, and there may be shared pathogenesis for migraine with visual aura and cardiac emboli," the authors, led by Michelle Androulakis, MD, MS, assistant professor of clinical neurology at the University of South Carolina, wrote.

Based on the findings, "clinicians might consider initiation of workup for assessment of factors predisposing to cardioembolism in migraine with visual aura patients, especially among those who have other coexisting stroke risk factors," said the study authors.

For their study, researchers analyzed data from the Atherosclerosis Risk in Communities (ARIC) study, an ongoing, prospective, longitudinal, community-based study investigating the etiology of atherosclerosis and atherosclerotic diseases. Among 12,758 participants averaging 59 years in age, the researchers identified 1,622 participants (12.6 percent) who had migraine and completed at least three clinical visits as part of the study. Of these, 3.6 percent had migraine with visual aura and 9 percent had migraine without visual aura.

Over a follow-up period of at least six years, they found that the link between migraine with visual aura and ischemic stroke was significant (p=0.014),.The risk was specific to cardioembolic stroke; migraineurs with visual aura had a significantly increased risk of cardioembolic stroke (p=0.003) but not of lacunar stroke (p=0.07) or of non-lacunar thrombotic stroke (p=0.09).

The authors speculated that luctuations in calcitonin gene-related peptide (CGRP) throughout a migraine attack may induce changes in coronary blood flow and velocity, in turn increasing the risk of atrial fibrillation and the risk of stroke. But, they wrote, "While it may be true in general that migraineurs, regardless of their status of visual aura, have elevated CGRP levels, we do not know if there is differential expression of CGRP levels in older migraineurs with or without visual aura."

They also pointed out that because the study did not enroll people younger than 45, the findings cannot be generalized to younger populations.

The researchers noted several limitations to their study, including that their algorithm for calculating stroke subtype required a cardioembolic source for classification of cardioembolic stroke, even though cardioembolism may not be the stroke etiology; and that they only counted visual aura as aura and may have excluded other auras, including sensory, motor, and brainstem aura.

Poorer children with epilepsy had worse social outcomes, but no difference in the clinical course of epilepsy or seizure relapse rates, compared to wealthier children with epilepsy, according to a new study published online on November 4 in Epilepsia.

Chronic diseases are generally more common and more severe in poorer families than in wealthier ones, the study authors noted. However, this association has not been established specifically for childhood-onset epilepsy. If such a link existed, the researchers added, it could provide a target for enhanced treatment and counseling. The results, however, suggest that family socioeconomic status does not affect disease severity for children with epilepsy – but it does affect their social outcomes.

"This information should be reassuring to families of low income and physicians who care for their children with epilepsy," the study's authors, led by Carol Camfield, MD, of Dalhousie University in Halifax, Nova Scotia, wrote. "Although long-term social outcome is significantly less successful in poor children, it remains an issue for children from all socioeconomic groups." And, they added, it speaks to the need for increased counseling services for poorer children.

For their study, researchers in Nova Scotia assessed data on 421 children who were enrolled in the Nova Scotia childhood-onset epilepsy cohort. All study participants were between one month and 16 years old and had new-onset epilepsy at the beginning of the study.

Over at least 10 years and as many as 25 years of follow-up, the researchers used a variety of measures to determine the clinical outcomes of children with epilepsy. These included the use of antiepileptic drugs; the total number of generalized tonic-clonic seizures, focal seizures; intellectual disability related to epilepsy; and major neurologic deficits related to epilepsy.

The researchers measured each child's socioeconomic status using three metrics: income (divided into five quintiles, with the first representing "poor," the second and third representing "adequate" income, and the fourth and fifth representing "well off"); family home ownership; and level of parent education.

Finally, researchers conducted interviews by telephone or face-to-face with each participant to assess their social outcomes. The interviews asked participants about their employment and education status, as well as their social status – whether they lived alone or had romantic relationships, for example – and any psychiatric diagnoses.

While the researchers found that income, family home ownership, and parental education did not affect clinical status, it did have an effect on social outcomes. Compared to the "well-off" group, children in the "poor" group were significantly more likely to have failed to complete high school (42 percent vs. 6 percent, p<0.001); to be unemployed (37 percent vs. 11 percent, p< 0.001); to be poor (56 percent vs. 19 percent, p<0.001); to have an inadvertent pregnancy (50 percent vs. 18 percent, p<0.001); and to have a psychiatric diagnosis other than attention-deficit hyperactivity disorder (34 percent vs. 14 percent).

Overall, wealthy children were significantly more likely to have no adverse outcomes at all (56 percent vs. 17 percent, p< 0.001), and poor children were significantly more likely to have had more than two adverse outcomes (33 percent vs. 9 percent, p< 0.001).

The researchers noted several limitations to their study: among them, the sample size may have been too small to detect minor variations in severity of epilepsy and their measures of socioeconomic status are not standardized.

Researchers have developed a new clinical risk stratification tool called the Surviving Penetrating Injury to the Brain (SPIN) scale based on an analysis of factors associated with survival from penetrating traumatic injury (pTBI). A report on the methodology for the scale was published in a paper online October 26 in Neurology.

The SPIN score, which has not yet been validated, may presently serve as "a preliminary tool that may provide guidance for physicians and families in their direction-of-care decision-making in patients with pTBI," and future external validation should expand its use, the study authors, led by Susanne Muehlschelegel, MD, MPH, critical care neurologist at UMass Memorial Medical Center, wrote.

The main cause of pTBI — gunshot wounds — is a serious public health problem, the study authors noted, adding that mortality rates for pTBI vary widely between trauma centers. A comprehensive, multivariable score for estimating survival after pTBI is necessary to identify ways to improve patient outcomes, they said.

For their study, the researchers retrospectively analyzed data on 413 pTBI patients using local trauma registries at two level-one trauma centers in the United States: the University of Maryland Shock-Trauma Center (n=377) in an urban setting and the UMass Memorial Medical Center, n=36) in a rural area. The patients were an average age of 33 years and were predominantly male; patients who were dead upon arrival at the trauma center were excluded.

They found that 175 patients (42.4 percent) survived to hospital discharge (the researchers' primary endpoint) and six months after pTBI (the secondary endpoint); there were no additional deaths at either center between hospital discharge and six months.

Additionally, the researchers found a wide range of factors associated with likelihood of survival. These included higher scores on the motor Glasgow Coma Scale subscore and pupillary reactivity, which were the two strongest predictors of survival. Injury that was not self-inflicted transfer status from another hospital, female gender, a lower Injury Severity Score, and a lower international normalized ratio were all independently associated with survival (p<0.001).

The researchers developed the SPIN score as a sum of individual points, with greater points allocated to stronger predictors of survival. However, they did not include radiologic factors in the scale, as these would have introduced too many parameters and limited predictive power. The score ranges from four to 52; higher scores indicate a stronger likelihood of survival.​

Among their findings, 98 percent of the patients with a SPIN score of 35 and above survived, while only 3 percent of patients with a score of 20 or below survived, and no patients with a score of 16 or below survived.

The researchers noted several limitations to their study, including the lack of score validation; the retrospective nature of the study, which may have resulted in incomplete collection of some outcome variables; and that most of the study participants were from the University of Maryland Shock-Trauma Center, which potentially biased the results toward an urban pTBI population.

Younger women — not older women — had an increased risk of stroke during pregnancy and the postpartum period compared to non-pregnant women of the same age, according to the results of a new study published online October 24, 2016 in JAMA Neurology.

Previous studies have suggested that the risk of PAS increases with older maternal age, probably due to increased prevalence of vascular risk factors like hypertension and diabetes, the study authors noted. But those studies rarely used age-matched non-pregnant control groups to determine age-related risks of PAS. The findings suggest that although there is a higher incidence of PAS among older women, pregnancy imparts an increased risk of stroke only for younger women compared to their non-pregnant, age-matched counterparts.

"Although older women have an increased risk of many pregnancy complications, a higher risk of stroke may not be one of them," the study authors, led by Eliza C. Miller, MD, a neurology resident at the Columbia University College of Physicians and Surgeons, wrote. "These results have potential implications for research aimed at better characterizing and preventing PAS and clinically in term of counselling patients."

For their study, the researchers used billing codes from the New York State Department of Health inpatient database to identify all women between the ages of 12 and 55 who were admitted to a hospital with a stroke between 2003 and 2012. The stroke types in the analysis included transient ischemic attack or ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, cerebral venous thrombosis, and nonspecified PAS, including postpartum stroke. The researchers used delivery codes to identify women who were pregnant or postpartum.

They found that 19,146 women were hospitalized with stroke during the study period; of these, 797 were pregnant or postpartum at the time of stroke. The incidence of PAS increased with age; for every 100,000 pregnant or postpartum women, PAS occurred in 14 women aged 12 to 24 years compared to 46.9 women aged 45 to 55 years.

However, the increase in PAS risk — as determined by the incidence risk ratio (IRR) generated using comparisons to age-matched non-pregnant control groups — decreased with increasing age. Among women in the 12-to-24 age group, non-pregnancy-associated strokes occurred in 6.4 of every 100,000 non-pregnant women, corresponding to an IRR of 2.2; by contrast, non-pregnancy-associated strokes occurred in 73.7 of every 100,000 non-pregnant women, corresponding to an IRR of 0.6.

A number of underlying stroke mechanisms may factor into the increased risk of stroke during pregnancy among younger women, the study authors noted. Compared to strokes in older people, strokes in young people often have rarer mechanisms. These include reversible cerebral vasoconstriction syndrome, which is linked to pre-eclampsia — a known risk factor for PAS. Additionally, inflammatory effects related to fetal DNA in maternal circulation may also raise stroke risk for very young women.

The authors noted several limitations to their study, including that the billing data used to assess outcomes were not specific, especially in regard to PAS, although the researchers validated the codes with medical records to keep false-negatives low. Also, other underlying risk factors or medication effects were not accounted for in the analysis.

High-frequency repetitive transcranial magnetic stimulation proved effective for treating motor but not nonmotor symptoms in people with Parkinson's disease and comorbid depression, according to a new study published online on October 5 in Neurology.

Transcranial magnetic stimulation noninvasively uses a magnetic field generator or coil placed near the patient's head to deliver electrical currents — generating changes in cortical excitability — to regions of the brain. Previous studies have shown that repetitive TMS (rTMS) improves motor symptoms of PD (when administered to the bilateral primary motor, or M1, cortex) and mood symptoms of PD (when administered to the left dorsolateral prefrontal, or DLPFC, cortex). The researchers hypothesized that administering rTMS to both areas might improve mood and motor symptoms, but the findings did not confirm their hypothesis.

"The combined protocol used here does not appear to be a promising therapeutic avenue, and future work should consider alternative protocols," the study authors, led by Miroslaw Brys, MD, PhD, associate professor of neurology at New York University Langone Medical Center, wrote.

For the multi-center, double-blind, sham-controlled, parallel-group study, researchers enrolled 61 patients with Parkinson's disease and depression; 50 patients completed all study visits. They randomized the patients to four groups: those who received rTMS over the bilateral motor (M1) cortex, the left dorsolateral prefrontal cortex (DLPFC), both cortices, or neither (sham therapy).

They measured the patients' scores on two tests – the Unified Parkinson's Disease Rating Scale (UPDRS) part III (UPDRS-III), a clinician-scored, monitored evaluation of Parkinson's disease motor symptoms, and the Hamilton Depression Rating Scale (HAM-D), a questionnaire that tests for mood symptoms of depression – at baseline and at one week, one month, three months, and six months after baseline.

They found that at one month after baseline, real M1 rTMS was associated with greater improvement in motor function compared to the sham procedure (p<0.05). However, they did not observe an improvement in mood symptoms in the DLPFC group compared to the sham group, and combining M1 and DLPFC stimulation did not result in an improvement of motor or mood symptoms.

Finally, they observed a greater antidepressant effect in the sham group than in the real DLPFC group, which was "likely the result of a pronounced placebo response."

The results, the study authors concluded, show that rTMS to the M1 cortex "appears promising for improving motor symptoms in PD." However, there was "no evidence of synergistic effects" resulting from combining rTMS to the left DLPFC or M1 cortices.

They noted that the duration of rTMS in their study was only 10 days, although major clinical trials of primary depression normally last 20 to 30 days, and in those trials, if often takes 15 days for patients to experience a significant response beyond the sham group. Therefore, they hypothesized, "a longer course of rTMS could still be beneficial for PD-associated depression," and "future work should consider longer-duration trials."

The study authors noted several important limitations. The trial was terminated early because of recruitment challenges, and they observed no efficacy in an interim trial of patients who received rTMS in both cortices, which reduced the study's statistical power.

Patients who had an acute stroke and comorbid aphasia upon admission to the hospital stayed more than one extra day at the hospital compared to patients who did not have a stroke, and they were more likely to have sepsis and other signs of neurological deterioration, according to a study published online on October 7 ahead of the print edition of Neurology.

Aphasia affects up to 38 percent of all acute stroke patients in the United States, the researchers noted. While much is known about how aphasia affects stroke patients after they are discharged from the hospital – with an associated increased risk of recurrent stroke and higher costs of care – comparatively little is known about how aphasia affects stroke outcomes during hospital admission.

The findings "demonstrate the underrecognized consequences of a communication disorder during acute stroke hospitalization," the study authors, led by Amelia K. Boehme, PhD, MSPH, assistant professor of epidemiology in neurology at the Gertrude H. Sergievsky Center at Columbia University, wrote.

For their study, the researchers assessed data from the Tulane Stroke Registry on 1,847 patients who presented at a comprehensive stroke center with an acute ischemic stroke or intracerebral hemorrhage between July 2008 and December 2014; 866 of the patients had aphasia when they were admitted to the hospital, as defined by the NIH Stroke Scale (NIHSS).

The researchers found that patients who had a stroke with aphasia upon hospital admission stayed at the hospital an average of 1.22 days longer compared to people who had a stroke and did not have aphasia.

They also found that stroke patients with aphasia were more likely to have complications related to a stroke (odds ratio 1.44, p=0.0174). The complications included a recurrent stroke, myocardial infarction, pulmonary embolus, deep vein thrombosis, sepsis, hospital-acquired infection, systemic bleeding, ventriculitis, and neurological deterioration.

The results show that aphasia "significantly add[s] to the burden of the health care system," the researchers concluded. Aphasia may add as much as $2.16 billion to annual health care costs in the United States, assuming a 30 percent aphasia rate among all stroke cases and a $9,100 cost per day of hospital admission, they added.

The study authors noted several limitations to their analysis. They were unable to delineate subtypes of aphasia, such as disorders of receptive or expressive language, using the NIHSS tool, and they did not know whether patients received aphasia therapy during their hospitalization for acute stroke.

Researchers have developed an assay that detects prion protein isoforms associated with sporadic forms of Creutzfeldt-Jakob disease in patient urine, opening the pathway for a noninvasive diagnostic test that could improve early diagnosis of the disease, they reported in a new study published online on October 3 in JAMA Neurology.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive prion disease with a median survival of around four months. Unlike the less-common variant Creutzfeldt-Jakob disease (vCJD), sCJD occurs without obvious exposure to an infectious source. Currently, the only available tests for sCJD are invasive, requiring a sampling of cerebrospinal fluid, and are often only given to patients who already have advanced disease. A recent report found that a urine assay was able to detect the abnormal prion proteins that accumulate as a result of vCJD; the current research suggests a similar assay can be used to detect sCJD.

"This is the first demonstration of an assay that can detect sCJD infection in urine or any target analyte outside of the central nervous system," the study authors, led by Connie Luk, PhD, postdoctoral fellow at the MRC Prion Unit at the University College London Institute of Neurology, wrote. "Urine detection could allow for the development of rapid, molecular diagnostics for sCJD."

For their cross-sectional study, researchers adapted an assay developed for vCJD detection in blood to detect disease-associated misfolded prion protein in the urine of patients with sCJD. The assay works by capturing disease-associated protein proteins in urine on a stainless steel matrix and detecting the presence of anti-prion protein monoclonal antibodies.

The researchers enrolled 37 patients with prion disease, of which 20 had sCJD; 34 patients with non-prion neurodegenerative diseases; and 91 healthy controls. They then collected urine samples from all study participants.

They found that eight out of 20 sCJD urine samples were positive, corresponding to 40 percent diagnostic specificity. The assay itself had 100 percent specificity for prion disease, since none of the the healthy controls or the patients with non-prion neurodegenerative diseases had false-positive results. The assay's sensitivity to vCJD was low, at only 7.7 percent.

The findings suggest that it may be possible to develop urine tests for other neurodegenerative diseases associated with protein misfolding, such as Alzheimer's disease, the study authors added.

"Our findings are in marked contrast to those recently reported using the technique of protein misfolding by cyclic amplification, where a high sensitivity for the detection of vCJD infection in urine was observed and yet none of the 68 patient samples from sCJD tested positive," the researchers wrote. "A critical limitation to the interpretation of this finding is that the assay method (protein misfolding by cyclic amplification) has never been convincingly demonstrated to detect sCJD and indeed no positive controls were included in this finding."

People who experience cluster headaches have a threefold increased risk of developing depression during their lifetimes, according to a new study published online on September 30 ahead of the print edition of Neurology.

Cluster headaches affect about one in 1,000 people and are distinguished by attacks of unilateral, periorbital, excruciating head pain. Eighty-five percent of patients experience headaches in clusters across periods of several weeks to months, and 25 to 55 percent of them report suicidal tendencies. Since cluster headaches share clinical and pathophysiologic features with migraine headaches, and because past research has linked migraines to an increased risk of depression, researchers sought to determine the link between cluster headaches and the lifetime incidence of depression.

The findings suggest that "early detection of comorbid depression in [patients with cluster headaches] may be important to prevent suicide in this painful primary headache disorder," the study authors, led by Mark A. Louter, MD, of Leiden University Medical Center in the Netherlands, wrote.

For their study, researchers identified 462 people participating in the Leiden University Cluster Headache Analysis program, an ongoing database of Danish people who have been diagnosed with a cluster headache according to the International Classification of Headache Disorders (ICHD)-III-beta criteria and, in almost all cases, by a physician. They also enrolled 177 healthy controls.

The researchers administered an extended cluster headache questionnaire that included questions about the frequency and duration of cluster headache attacks, symptoms of lifetime depression, and incidence of sleeping problems. The questionnaire included the Hospital Anxiety and Depression Scale the Center for Epidemiologic Studies Depression scale, the Pittsburgh Sleep Quality Index (PSQI), and supplementary questions.

They found that participants with cluster headaches had three times higher odds of developing depression compared to the controls. They also scored higher on the PSQI, indicating worse sleep quality. People who had active cluster headache attacks — defined as having had at least one cluster headache attack in the month preceding the survey — were more likely to have depression at the time of the survey compared to people who had been attack free for at least one month.

Additionally, the study authors found that only 17 percent of people who experienced cluster headaches and fit the criterion for current depression were treated with antidepressants, suggesting that depression was "considerably underdiagnosed and undertreated in cluster headache patients."

The results, the study authors concluded, demonstrate that cluster headaches pose a high risk of depression, and that poor sleep may at least partially explain the incidence of depression in their study cohort. They hypothesized that the relentlessly recurring pain of cluster headaches may also cause despair and stress, in turn leading to depression. In addition, they proposed that dysfunction in the hypothalamus may play a role, since depression, sleep disorders, and cluster headaches have all been associated with functional and structural changes in the hypothalamus.

The researchers noted several limitations to their study, including its cross-sectional design, which prevented them from drawing a firm conclusion about the direction of the comorbidity; that the study participants were largely Dutch/Caucasian, young, and well-educated, which limits extrapolation of the findings to a larger and more diverse population; and that depression was measured with questionnaires that were not specifically designed to diagnose depression in individuals.

People aged 80 and older have unique characteristics that merit their inclusion in clinical stroke trials, according to an analysis published online on September 27 in Stroke. This age group is largely excluded from stroke trials due to a fear of poor outcomes and high comorbidities, but the study authors argue that many people in this age group are living longer and enjoying a high quality of life. Including them in future stroke trials would improve participation in trials and allow findings to be generalized to a greater population.

"Enrollment of very elderly and extreme elderly subjects in clinical stroke research is feasible and desirable," wrote the study authors, led by Nerses Sanossian, MD, associate professor of neurology and director of the Roxanna Todd Hodges Stroke Program at the University of Southern California. "Inherent differences among the very elderly provide further evidence of the importance of their inclusion in research."

STUDY PARAMETERS

Researchers analyzed results from the phase 3 Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial, which enrolled 1,700 participants in Los Angeles, including 1,210 nonelderly (under 80 years), 490 very elderly (80 to 89 years old), and 60 extreme elderly (90 years old or above) participants.

STUDY RESULTS

People in the very elderly group had more comorbidities than the nonelderly, including hypertension (85 percent vs. 75 percent, respectively; p<0.01) and coronary artery disease (28 percent vs. 18 percent, p<0.01). However, behavioral risk factors like drinking and smoking were more common in the nonelderly group than in the very elderly. Nonelderly people also had higher blood pressures. The extreme elderly were more likely to have atrial fibrillation than the rest of the population.

Similar percentages of all three cohorts received various reperfusion therapies (including endovascular intervention or IV tPA), and the time between stroke onset and treatment was also similar. However, door-to-imaging times were longer in the very elderly versus the rest of the population (42 minutes vs. 33 minutes, p=0.048).

Finally, a significant number of very elderly and extreme elderly participants were functional at 90 days post-stroke (40 percent and 25 percent, respectively) defined by their level of disability as assessed by the modified Rankin scale.

STUDY CONCLUSIONS

The results, the study authors wrote, demonstrate that including the very and extremely elderly populations in clinical stroke trials could help researchers better understand the efficacy of various new and existing stroke treatments for all age groups.

OUTSIDE ANALYSIS

In an accompanying editorial, Richard I. Lindley, MBBS, MD, professor of geriatric medicine at the University of Sydney in Australia, praised the analysis, noting that 29 percent of the participants were at least age 80, which matches the epidemiology of stroke in developing countries.

Patients with large-vessel acute ischemic stroke who were treated with endovascular thrombectomy within 7.3 hours of symptom onset had better three-month outcomes than those who received IV tPA alone, according to a new meta-analysis of five randomized trials published online on September 26 in the Journal of the American Medical Association. The 7.3-hour window was significantly longer than the current guideline recommendation of six hours, the researchers found.

NEW TIME-TO-TREAT WINDOW

Previous trials, including those reviewed in the meta-analysis, have demonstrated that endovascular thrombectomy with second-generation devices, including stent retrievers, leads to better outcomes compared to IV tPA alone, the study authors wrote. But this analysis is the first to demonstrate that among patients who underwent thrombectomy, earlier time to treatment was associated with better outcomes, and to identify an optimal treatment window.

The 7.3-hour time window is a good starting point and allows for improvement in performing routine endovascular therapies, according to the study authors, led by Jeffrey L. Saver, MD, professor of clinical neurology at the University of California at Los Angeles and director of the UCLA Stroke Unit.

STUDY PARAMENTERS

For the meta-analysis, called the Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES), researchers pooled demographic, clinical, and brain imaging data on 1,287 adults from five phase 3 trials testing the efficacy of thrombectomy versus IV tPA for treating acute ischemic stroke with large-vessel occlusion. Patients were randomized an average of 196 minutes after symptom onset: 634 participants were assigned to the endovascular group and 653 to the medical therapy group. The researchers used the modified Rankin scale (mRS) – a six-point scale measuring degrees of disability and dependence, with higher scores indicating greater disability – to assess patients' outcomes at three months.

STUDY RESULTS

Endovascular intervention was associated with a "substantially lower" level of patient disability at three months compared to IV tPA alone (mRS scores of 2.9 compared to mRS scores of 3.6, respectively).

Additionally, the sooner patients were treated with endovascular thrombectomy, the better their three-month modified Rankin scale scores. For patients who received reperfusion at three hours after symptom onset, 64 percent were functionally independent after three months compared to 46 percent of those who received reperfusion eight hours after symptom onset.

Overall, among the 390 patients who achieved substantial reperfusion with endovascular thrombectomy, every one-hour delay was associated with a greater degree of disability and less functional independence; however, delays in reperfusion were not associated with changes in mortality. Thrombectomy maintained a statistically significant advantage in three-month outcomes until 7 hours and 18 minutes after the procedure began (defined as the expected arterial puncture time).

CONCLUSIONS

The sooner patients with acute ischemic stroke due to a large-vessel occlusion undergo reperfusion, the better their outcomes, the study authors suggested. They estimated that for every 1,000 patients who received endovascular reperfusion, every 15-minute reduction in emergency department door-to-reperfusion time would result in 39 patients being less disabled at three months, including 25 who would achieve functional independence.

The study authors noted a number of limitations, including a potential bias caused by differences in entry criteria and patient characteristics between the five trials and the fact that functional outcomes were assessed only at three months, even though further improvements may have occurred after that.

Look for further coverage of this meta-analysis in an upcoming edition of Neurology Today.

Researchers have identified biochemical markers in the cerebrospinal fluid of individuals with post-concussion syndrome, which could be used to assess the extent of damage caused by mild traumatic brain injury, according to a new study published online on September 19 ahead of the print edition of JAMA Neurology.

A small subset of individuals who experience one or more concussions develop post-concussion syndrome, neurological symptoms that persist for more than three months, the study authors noted. However, no objective biomarkers exist to quantify the extent of neuronal damage or other central nervous pathology in people with PCS.

"Measurement of these biomarkers may be an objective tool to distinguish individuals who are at risk of developing persistent PCS or progressive neurodegeneration," the study authors, led by Pashtun Shahim, MD, PhD, of the University of Gothenburg in Sweden, wrote.

STUDY PARAMETERS

For the multicenter, cross-sectional study, the researchers enrolled 16 professional Swedish hockey players who had repeated concussions and multiple post-concussion symptoms for at least three months and fulfilled the criteria for PCS as defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). They matched them with 15 healthy controls. Nine of the participants with PCS had symptoms for more than one year, and the remaining seven returned to play within one year.

The results suggest that NF-L and Abeta-42 are potentially useful measures of neuronal damage and axonal white matter injury in people with PCS.

The authors acknowledged the small sample size, which prevented them from examining the associations of specific biomarkers with specific symptoms of PCS, including behavioral, cognitive, and/or neurological changes. Additionally, the researchers did not have data from diffuse tensor MRI or amyloid tau PET scans to corroborate the biomarker findings.​

About one quarter of people who came to the hospital with an acute ischemic stroke within two hours of symptom onset and were eligible to receive intravenous tissue plasminogen activator (tPA) did not receive it, according to a new study of the Get With The Guidelines-Stroke (GWTG) registry published online on September 14 ahead of the print edition of Neurology. Eligible patients were more likely to receive tPA if they were treated at a primary stroke center, while women and minorities were less likely, the study found.

"As has been reported previously, treatment at a primary stroke center is one of the strongest predictors of tPA use," the study authors, led by Steven R. Messé, MD, FAAN, associate professor of neurology at the University of Pennsylvania, wrote. "To improve thrombolysis rates, continued development of systems of care for stroke should remain a high priority."

STUDY METHODOLOGY

For their study, the authors accessed data on stroke treatment from GWTG, an ongoing, voluntary, national registry comprising more than 1,800 hospitals and 2.5 million patient records. They identified all patients in the registry who were admitted to a hospital with acute ischemic stroke within two hours of stroke onset, had no known contraindications to tPA, and were treated within three hours.

FACTORS DETERMINING TPA USE

They found that of 61,698 patients who met those criteria, 75 percent received tPA within three hours. The remaining 25 percent were not treated with tPA. Those who were not treated were more likely to be older, female, black or another nonwhite race, and generally had more vascular risk factors for stroke, including coronary artery disease, diabetes, hypertension, and prior stroke.

In addition, patients who were not treated with tPA were less frequently transported to the hospital by EMS and had a longer delay in door-to-CT time. Hospitals that didn't treat eligible patients with tPA tended to have fewer beds, fewer annual ischemic stroke admissions, and were less likely to be certified as primary stroke centers by the Joint Commission, the independent health care evaluation body that awards certifications in partnership with the American Heart Association/American Stroke Association.

WAYS TO INCREASE TPA USE

The results, the study authors concluded, provide further evidence that becoming certified as a primary stroke center in accordance with GWTG/Joint Commission guidelines may increase rates of tPA use for eligible ischemic stroke patients. Other factors that may help include educating patients and medical staff about vascular risk factors for stroke, increasing use of EMS in transporting patients to hospitals, reducing door-to-CT time, and improving tPA treatment rates for eligible nonwhite and female stroke patients.

The authors noted a number of limitations, including that some patients who were considered eligible were not in fact eligible because their doctors failed to record contraindications, and that patients who were treated after three hours were excluded, even though current guidelines allow for tPA treatment in a three-to-four-and-a-half-hour time window.

People who had a stroke had a four-fold increased risk of developing depression within two years compared to a control population who did not have stroke, and those who had depression prior to the stroke or who had a severe stroke had an especially high risk, according to a new study published online on September 12 ahead of the print edition of JAMA Psychiatry.

Previous studies have consistently associated stroke with depression, but few have included a control population, and many had small sample sizes or did not examine associations between post-stoke depression and sociodemographic factors or stroke subtype, the study authors noted. The current findings suggest that depression is common after stroke, is related to stroke subtype, and is an independent risk factor for mortality.

"The high rates of depression in patients with stroke indicate that a large number of deaths occurring during rehabilitation may be attributable to this condition," the study authors, led by Terese S. H. Jørgensen, MSc, of Copenhagen University in Denmark, wrote. "[This] suggests that clinicians should remain vigilant concerning this risk, especially in patients with a history of depression and a high number of somatic comorbidities."

For their analysis, researchers analyzed data from seven Danish nationwide registries. They matched 157,243 patients who had a first-time hospitalization for stroke between 2001 and 2011 with a reference population of 160,236 patients. They confirmed depression through a clinical diagnosis or by the filling of a prescription for an antidepressant.

Among those who did not have depression at the start of the study, the researchers found that depression occurred within two years after stroke in 34,346 patients (25.4 percent) in the stroke group and within two years of the start of the study in 11,330 patients (7.8 percent) in the control group, corresponding to a four times greater overall risk of depression after stroke.

More than half of the cases (17,690) of depression in the stroke group occurred during the first three months after stroke, whereas depression occurred within the first three months in less than a quarter of cases (2,449) in the reference group. This corresponded to an eight times greater risk of depression after stroke during this time period, the study authors added.

Patients who had a severe stroke had the highest risk of depression, while patients who had a transient ischemic attack had a three times lower risk of depression compared to those with a stroke diagnosis.

Several risk factors were associated with depression in both the stroke and control populations, including older age; female gender; and a high level of somatic comorbidities, including diabetes and coronary heart disease. However, the relative risk of these associations was higher in the controls than in those who had a stroke.

Additionally, the researchers found that depression was associated with mortality in both populations, but that depression-related relative mortality was about twice as high in the control group compared to the stroke population. This, the study authors wrote, "suggests different etiologic mechanisms" underlying depression after stroke and depression arising without a known prior somatic illness. A number of theories – including the location of the stroke lesion, vascular depression, inflammation, and neuroplasticity – may explain the differing etiology, but the study was not able to examine those theories, the authors added.

The study authors noted several limitations, including a lack of information on the lesion location, which allows only indirect support for etiologic mechanisms of post-stroke depression. In addition, they pointed out that the antidepressant prescriptions, used to define most cases of depression, could have been for other comorbidities.

Look for more in-depth coverage of this study in an upcoming issue of Neurology Today.

Aducanumab, a human monoclonal antibody that selectively targets amyloid-beta (Abeta), appeared to reduce Abeta plaques in patients with prodromal or mild Alzheimer's disease (AD) over a 54-week course of intravenous treatment, according to the results of a randomized, double-blind, placebo-controlled phase 1b trial that were published online on September 1 in Nature.

In a transgenic mouse model of Alzheimer's disease (AD), researchers found that aducanumab entered the brain, binded parenchymal Abeta, and reduced soluble and insoluble Abeta in a dose-dependent manner. The findings add support to the amyloid hypothesis of Alzheimer's neuropathology, they said, which posits that Abeta-related toxicity is a primary cause of Alzheimer's-related neurodegeneration. "Together, the clinical and preclinical data support continued development of aducanumab as a disease-modifying treatment for Alzheimer's disease," they wrote.

For the PRIME study, researchers enrolled 165 patients at 33 sites in the United States between October 2012 and January 2014. The patients had prodromal or mild AD with brain Abeta pathology confirmed by molecular positron emission tomography (PET) imaging. The patients were randomized to receive monthly intravenous infusions of aducanumab at doses of 1, 3, 6, or 10 mgkg-1 or placebo for one year.

The researchers used PET imaging with florbetapir to measure changes in Abeta plaque accumulation in the brain. They found that after 54 weeks of treatment, the mean PET standard uptake value ratio (SUVR) decreased significantly from the baseline score of 1.44 (p<0.001) in the aducanumab group, compared to a minimal change for the placebo group. Additionally, they found that Abeta reduction increased in a dose-dependent manner.

The reductions in Abeta PET SUVR composite scores in patients treated with aducanumab were similar in patients with mild and prodromal forms of Alzheimer's disease, and between apolipoprotein E (ApoE) ε4 carriers and non-carriers, the study authors added.

Administration of aducanumab was also associated with improved clinical outcomes, as measured by a dose-dependent slowing of clinical depression on both the Clinical Dementia Rating – Sum of Boxes scale (a commonly used scale for scaling dementia severity, with scores ranging from 0 to 18 and higher scores indicator greater dementia severity) and the Mini Mental State Examination scale (a 30-point questionnaire that measures cognitive impairment, with lower scores indicating greater impairment).

Common adverse side effects included headache, urinary tract infection, and upper respiratory tract infection. A minority of patients experienced amyloid-related imaging abnormalities, primarily ARIA-vasogenic edema (ARIA-E), with higher doses linked with a higher incidence of ARIA-E, early in the course of treatment. This adverse effect was classified as severe, although no patients were hospitalized.

The study authors speculated that the drug may work by slowing release of soluble Abeta oligomers —which have been hypothesized to be the primary toxic species of Abeta — into the neuropil, limiting their toxic effect on neurons.

The authors noted several study limitations, including the staggered parallel-group design, the small sample size, and the limited region of study (only the United States).

Look for more in-depth coverage of this study in a forthcoming edition of Neurology Today.

A significant proportion of child neurologists and neurodevelopmental specialists in the United States are dissatisfied with their compensation and benefits, and they say the workforce is understaffed and growing too slowly to meet projected needs, according to an electronic survey conducted jointly by the American Academy of Pediatrics (AAP) and the Child Neurology Society (CNS).

The results of the survey were published online on August 26, 2016 ahead of the print edition of Neurology.

For their analysis, members of the AAP/CNS Task Force surveyed 523 practicing physicians and 97 trainees. Most of the respondents practiced in academic medical centers and had a primary or secondary subspecialty in child neurology, neurology, and/or neurodevelopmental disabilities; 85.5 percent of them were in active clinical practice.

Among responses, the survey showed that medical school loans placed a considerable financial burden on many respondents — most respondents who took out loans had at least $50,000 in medical school debt. And only about 26.5 percent of those surveyed were positive or extremely positive about their compensation, compared to a larger 42.4 percent who were negative or extremely negative.

A primary concern of the task force was workplace shortages in child neurology. The study authors noted that the number of training positions in child neurology has increased from an average of 80 per year in the 1997-2002 period to 154 positions in 2014, and the number of active members in the CNS has grown steadily since the 1980s. While these numbers might seem encouraging, the authors noted that the compound annual increase in CNS membership was just 3.37 percent, which they considered a slow rate of growth.

The study authors noted that a decreasing number of child neurologists and neurodevelopmental disabilities specialists are practicing in independent practices – instead, a growing number work at hospitals or academic physician organizations. As a result, the study authors suggest, they may be held to "arduous accountability standards," and they may have reduced leverage in negotiations about salary or their professional environments.

And while nearly half of the respondents reported clinical research activity, less than 10 percent of them conduct basic research, suggesting that the physician-scientist workforce in child neurology is becoming an "endangered species," the task force said. Many child neurologists do not receive the specialized training they want or need; for example, of the 402 respondents who said they managed patients with epilepsy, only 65 percent said they could read an electroencephalogram (EEG), and only 42 percent were formally trained in a neurophysiology or epilepsy fellowship.

Recruitment and mentoring of trainees by current child neurologists, as well as advocacy for recognition of the values of their contributions, are crucial to maintaining growth in the field, the study authors concluded. Additionally, they expressed their hope that programs like the NIH Neurological Sciences Academic Development Award will help foster the growth of early career physician-scientists through grants and career development programs.

The task force noted as a limitation that the 38 percent overall response rate was substantially lower than the response rate, 65 percent, to an earlier (2002) study, which may be related to the fact that the survey was sent electronically. In addition, they wrote, the fact that a significant proportion of respondents were trained before 1994 may have partially obscured demographic shifts.

Intravenous thrombolysis with tissue plasminogen activator (tPA) is safe and effective for treating acute ischemic stroke when administered through a telestroke network within three hours after stroke onset, according to a new systematic review and meta-analysis published online on August 26 ahead of the print edition of Neurology.

"While telestroke has repeatedly proven to convey [stroke] expertise to many rural hospitals worldwide, evidence for efficacy on clinical outcomes is still sparse," the study's authors, led by Jessica Kepplinger, MD, neurologist at Dresden University Stroke Center in Dresden, Germany, wrote. "This meta-analysis confirmed the safety of IVT delivered through telestroke networks."

The researchers conducted a systematic review of seven studies totaling 1,863 patients – including two randomized controlled trials (n=72) and five nonrandomized, observational studies (n=1,791) – that compared telestroke-guided intravenous thrombolysis (IVT) with IVT administered at a stroke center. In order to qualify for the analysis, patients with acute ischemic stroke had to be treated with IV tPA through a hub-and-spoke stroke care network, in which stroke centers (hubs) are connected via telemedicine to hospitals without specialized stroke centers (spokes). The studies measured rates of symptomatic intracerebral hemorrhage after tPA administration, mortality at three months, and functionality at three months; all studies used the modified Rankin scale (a scale from 0 to 6, with higher scores corresponding to greater disability or dependence) to measure functionality.

Rates of symptomatic intracerebral hemorrhage were similar between patients who were treated with telemedicine-guided thrombolysis and patients who received tPA onsite at a stroke center (p=0.978). Additionally, there was no between-group difference in three-month mortality rates (p=0.806) and three-month functional independence scores (p=0.565). The results remained consistent after a sensitivity analysis.

The findings, the study's authors wrote, demonstrate that the "safety and efficacy of IV tPA delivered through telestroke networks is not inferior to tPA administered at specialized stroke centers for treatment of [acute ischemic stroke] in the three-hour time window."

They noted, however, that all available studies restricted IVT to a three-hour time window, "leaving a gap in our understanding" of the safety and efficacy of IVT in an expanded, three-to-four-and-a-half-hour time window.

The study authors noted several limitations, including the small number of included studies and the fact that data from two of the included studies overlapped. They also noted that most of the included studies did not adjust for potential confounders, including stroke severity, age, and onset-to-treatment time, and that the studies varied in their definitions of safety and efficacy outcomes.

In an accompanying editorial, Bart M. Demaerschalk, MD and Steven R. Levine, MD, FAAN praised the results of the study, concluding that "In the right hands, we believe the evidence is in" supporting the use of IV tPA through telestroke networks in a three-hour time window. They noted, however, that much attention has been paid to the efficacy of telemedicine in the diagnosis and decision-making stages of care. "The time has come," they concluded, "to examine remotely managed stroke patients in the intensive care unit, the stroke unit, and the hospital floor."

Calcium supplementation was associated with an increased risk of developing dementia in elderly women with cerebrovascular disease, according to the results of a five-year observational study published online on August 17 ahead of the print edition of Neurology. The risk was mainly confined to women who had a history of stroke or who had white matter lesions on brain imaging, the study authors said.

Some studies have associated increased intake of supplemental calcium, taken to prevent osteoporosis, with an elevated risk of vascular events, which also has been associated with the risk of Alzheimer's disease and dementia, the study authors noted.

Researchers at the University of Gothenburg in Mölndal, Sweden followed 700 older women between the ages of 70 and 92 who did not have dementia at the beginning of the study. The study sample was derived from the Prospective Population Study of Women and the H70 Birth Cohort Study. Among all study participants, 108 women had a history of stroke, and 316 of the 447 participants who had computed tomography (CT) scans had white matter lesions, a marker of cerebrovascular disease.

Ninety-eight of the women were treated with calcium supplements over the five-year follow-up period, while 602 women were not given calcium supplements. At the end of the follow-up period, geriatric psychiatrists evaluated the study participants using psychiatric examinations and interviews. They diagnosed dementia according to DSM-III-R criteria and Alzheimer's disease, as well as criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.

The researchers found that calcium supplementation was associated with the development of dementia in women with a history of stroke (p=0.020), but not in women without a history of stroke (p=0.381). Additionally, calcium supplementation was associated with dementia in women who had white matter lesions on CT scans (p=0.011); there was no association found in women taking calcium supplements who did not have white matter lesions (p=0.351).

"This association was mainly confined to individuals with cerebrovascular disease at baseline," the study authors, led by Jürgen Kern, MD, PhD, neurologist at the Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg.

The study authors hypothesized that calcium supplements "may potentiate changes in the vessel walls in individuals with vascular disease, leading to ischemia and hypoperfusion" or that calcium supplements may stimulate vascular calcification by abnormal extraosseous deposition in atherosclerotic plaques. They noted that that study participants' levels of serum calcium – a measure of calcium in the blood – increased sharply after they took the supplements, which may have altered blood flow in the brain, in turn increasing dementia risk.

Dietary calcium is not associated with the same vascular risks as calcium supplementation, the study authors noted. They hypothesized the difference in risk effect between the two may be attributable to corresponding changes in serum calcium levels, since "dietary intake does not increase the serum calcium levels to the same extent as supplements."

The researchers noted that among several limitations, the study was small and observational; they had no information on dietary calcium intake; the participants' levels of serum calcium, or whether their use of calcium was casual or persistent.

A history of stroke was associated with a two-fold increased risk for both familial and sporadic forms of late-onset Alzheimer's disease (LOAD), according to an analysis of data from two longitudinal studies that was published online August 15 in JAMA Neurology. But hypertension was associated with decreased disease risk, and there was no association found between type 2 diabetes and LOAD.

Previous studies have found an association between cerebrovascular and cardiovascular risk factors — such as type 2 diabetes, hypertension, smoking, lipid disorders — and LOAD, but little was known about causal associations and the timing of cardiovascular and cerebrovascular disease and LOAD, the authors noted.

The researchers, led by Giuseppe Tosto, MD, PhD, assistant professor of neurology at Columbia University Medical Center, wanted to parse out the contribution of cardiovascular risk factors and stroke to the risk for LOAD.

They analyzed clinical outcomes from a total of 6,553 adults — participants in National Institute on Aging Late-Onset Disease/National Cell Repository for Alzheimer Disease family study and the multiethnic community-based Washington Heights-Inwood Columbia Aging Project — who met several criteria for familial AD.

To explain the finding of an inverse association between hypertension and LOAD risk, the authors hypothesized that "high blood pressure in late life may protect against LOAD" and antihypertensive treatments – including diuretics, beta-blockers, calcium channel blockers, and others — may confer a "protective effect."

The findings reflect what the researchers referred to as a phenomenon of "inconsistent mediation," in which a direct pathway — hypertension decreases stroke risk — and an indirect pathway —hypertension leads to stroke, which leads to increased stroke risk — operate simultaneously.

The results suggest the importance of interventions targeting modifiable risk factors in LOAD and the complex relationships between hypertension and LOAD, the study authors wrote, adding that more longitudinal studies and a larger set of variables – different classes of treatments — need to be studied.

The study authors noted a number of limitations: the absence of confounders – including smoking, physical activity level, and body mass index – in analyses; the fact that several predictors were self-reported, including heart disease and medications, which may have contributed to a bias; and that history of stroke did not account for multiple stroke events.

People who have a stroke at a young age may have a higher risk of developing cerebral small vessel disease. Moreover, cerebral aging may be accelerated by 10 to 20 years in these patients, suggesting an increased vulnerability to vascular risk factors, according to a study published online on August 12 ahead of the print edition of Neurology.

"The suggested increased vulnerability supports the need for accurate identification of vascular risk factors at presentation and immediate treatment accordingly, even in these often young patients," the study authors, led by Renate M. Arntz, MD, PhD, professor of neurology at Radmoud University Medical Center in Nijmegen, the Netherlands, wrote.

Researchers in the Netherlands evaluated 337 people between the ages of 18 and 50 who had had an ischemic stroke or a transient ischemic attack (TIA), as well as 90 controls who had identical vascular risk factors as the stroke group but no history of stroke. All were participating in the Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study, a prospective cohort study designed to investigate the causes and consequences of young stroke. The researchers used MRI scans at follow-up to assess the presence of vascular risk factors, including lacunes, microbleeds, and white matter hyperintensity (WMH) volume.

After a mean follow-up of 9.9 years, they found that 81 patients who had had a stroke at a young age (24 percent) had at least one lacune on MRI, compared with 4 controls (4.5 percent, p<0.001). They found no difference in microbleeds between patients who had had a stroke and controls. However, the stroke cohort had an average of 1.5 mL more WMH volume compared to controls (p<0.001).

The stroke cohort had an elevated risk of lacunes and higher WMH than controls even after adjusting for confounders, including age, sex, smoking, diabetes, and hypertension, the researchers noted. Additionally, the stroke group already had the same volume of WMHs on average 10 to 20 years earlier in life than controls with identical vascular risk factors, suggesting that cerebral aging may be accelerated in young stroke patients.

The findings have "prognostic implications," the study's authors suggested. Cerebral small vessel disease has been linked with other diseases independent of stroke, including depression and cognitive impairments, they noted. Long-term follow-up of young patients who have a stroke is therefore "of utmost importance," they concluded.

The study's authors noted several study limitations, including possible underestimation of WMH volume in the young stroke group due to incomplete follow-up by smokers in that group; their inability to determine incident small vessel disease, which made the study cross-sectional; and the possible influence of confounders, although the researchers attempted to adjust their analyses to eliminate the most important confounders for small vessel disease.

Most people who had a mild traumatic brain injury (TBI) regained the ability to make reasoned medical decisions twelve months later, but many who had a moderate/severe TBI had lingering deficits that inhibited medical decision-making at one year, according to a new study published online on August 10, 2016 ahead of the print edition of Neurology.

People who sustain a TBI have a number of treatment decisions to face during their stay in the hospital, during rehabilitation, and during long-term recovery, including managing medications, following advance directives, or treating orthopedic injuries and secondary complications, the study's authors noted. The researchers had previously studied and found impairments at the time of injury in MDC in complicated mild and moderate/severe TBI groups, but they had not assessed their longer-term recovery.

"Clinically, the current findings underscore the importance of evaluating MDC soon after injury and over time in all individuals with TBI," the study authors, led by Kayla A. Steward, BS, of the University of Alabama at Birmingham, wrote.

Researchers recruited 111 people who were being treated for TBI at an inpatient/outpatient rehabilitation unit and at an outpatient neurology department and 66 healthy controls for the study. They divided participants in the TBI group into several subgroups based on severity of injury: those with mild TBI (n=28), complicated mild TBI (n=23), and moderate/severe TBI (n=60).

They assessed the study participants' ability to make medical decisions at one month, six months, and 12 months post-injury using the Capacity to Consent to Treatment Instrument (CCTI), a psychometric instrument that presents hypothetical medical problems with symptoms and asks patients to select a treatment option. The instrument measures five standards of consent: expressing a treatment choice (expressing choice); appreciating the personal consequences of a choice (appreciation); providing rational reasons for a choice (reasoning); understanding the treatment choices and respective risks/benefits (understanding); and ability to make a reasonable treatment choice (reasonable choice).

They found that compared with controls, no TBI group showed impaired MDC expressing choice or reasonable choice at any timepoint. However, they observed notable differences among the three TBI groups in certain aspects of decision-making over the first year.

Participants with mild TBI recovered MDC relatively quickly, and most regained full MDC after six months. Participants with complicated mild TBI showed more initial MDC impairment and slower recovery than those with mild TBI, but approached full recovery at 12 months. However, for participants with moderate/severe TBI, all three complex consent standards — appreciation, reasoning, and understanding — remained "below the level of control performance" at one year.

Among findings, less than 20 percent of participants with mild TBI continued to have impaired appreciation and understanding, and no more than 14 percent of participants with complicated mild TBI continued to have impaired appreciation, reasoning, or understanding one year post-injury. By contrast, a "large proportion" of participants with moderate/severe TBI remained impaired on all three consent standards one year after injury: 17 percent had impaired appreciation, 25 percent had impaired reasoning, and 50 percent had impaired understanding.

The study's authors added that in all groups, most recovery took place during the first six months after the injury, and recovery stabilized after six months with limited MDC improvement between six and 12 months.

The results, the study's authors wrote, support the "need for continual monitoring of MDC in those with more severe head injuries for at least a year post-injury."

The study's authors noted several trial limitations, including their inability to compare outcomes between moderate and severe TBI (due to a lack of participants with moderate injuries); the relatively short duration of the study; and the fact that a quarter of the study participants did not complete all three visits.

Thymectomy combined with prednisone improved clinical outcomes in patients with nonthymomatous myasthenia gravis over a three-year period compared to prednisone alone, according to a new study published August 11 in the New England Journal of Medicine.

The randomized, controlled, multicenter trial is the first of its kind to assess the benefit of thymectomy versus medical treatment alone for myasthenia gravis, an autoimmune neuromuscular disease that can cause muscle weakness, vision problems, and other symptoms.

Thymectomy has been used to treat nonthymomatous myasthenia gravis — a form of the disease that does not include a thymoma, or chest tumor — for 75 years, the study's authors noted, but observational and retrospective studies were limited and have not shown a clinical benefit to surgery versus medical therapy alone. Because the neurologic disease is so rare, it was challenging to enroll enough patients to conduct a randomized, controlled study to ascertain the benefit of the surgery and identify "the clinical characteristics of the patients who should be offered the procedure," the study's authors added.

Previous nonrandomized studies had bias problems, said Gil I. Wolfe, MD, FAAN, Irvin and Rosemary Smith chair of the department of neurology at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo of the State University of New York and chief study author, in a press release accompanying the study. The new findings confirm that thymectomy is beneficial, the authors noted.

The researchers enrolled 126 patients who had myasthenia gravis for less than three years in the MGXT trial. The participants were randomized to receive alternate-day prednisone alone (n=60) or thymectomy plus alternate-day prednisone (n=66). The primary outcomes were a reduction in the Quantitative Myasthenia Gravis score – a 13-item, 39-point scale of muscle weakness, with higher scores indicating more severe weakness, and a reduction of 2.3 points signifying improved clinical status – and a significant reduction in prednisone dosage.

They found that patients in the thymectomy group had "significantly lower" Quantitative Myasthenia Gravis scores compared to patients in the prednisone group (a difference of 2.85 points, p<0.001) over the three-year study period. They also found that patients in the thymectomy group had lower prescribed dosages of prednisone (44 mg versus 60 mg in the prednisone-only group, p<0.001).

In addition, patients in the thymectomy group had fewer hospitalizations for exacerbations of myasthenia gravis (9 percent) than those in the prednisone-only group (37 percent, p<0.001). Among patients who were hospitalized, those in the thymectomy group had fewer cumulative days in the hospital (8.4±8.6 days) compared to those in the prednisone-only group (19.2±24.5 days; p=0.09). Compared to the prednisone-only group, patients in the thymectomy group had better scores on the Myasthenia Gravis Activities of Daily Living scale, an eight-question survey that assesses interference of myasthenia gravis symptoms with daily life.

The results, the study's authors wrote, provide evidence "supporting the use of thymectomy for improving clinical outcomes and reducing the need for immunosuppressive therapy" for patients with myasthenia gravis.

The study's authors noted several limitations, including the single-blind nature of the study and the pill-count method used to assess medical outcomes, which was "not a precise measure of actual intake."

In an accompanying editorial, Allan H. Ropper, MD, professor and executive vice chair of neurology at Harvard Medical School, noted that the results of the trial "reflect the difficulty in capturing these fluctuating and fatigable myasthenic symptoms." The clinical outcomes were better in the thymectomy group, he said, but the "absolute differences were moderate," and the main results were supported by secondary outcomes, showing that more patients in the thymectomy group had "minimal manifestations" by three years and a lower rate of need for immunosuppression with azathioprine.

While the findings "will be useful in counseling patients," he cautioned that they "offer no further clarity" for the selection of patients receiving thymectomy because secondary analyses did not show relative benefits based on gender or age. "Nevertheless, the appeal of a virtual cure by means of thymectomy is likely to persist because of the unappealing alternative of a long-term commitment to the use of glucocorticoids and immunosuppression," he said.

A handheld noninvasive vagus nerve stimulation (nVNS) therapy was found to be safe and well-tolerated for treating chronic migraine, according to a study published in the August 2 online edition of Neurology. The prospective, sham-controlled pilot study did not find that nVNS significantly changed the number of headache days at the two-month endpoint, but those who continued on the open-label treatment for six months did experience a significant reduction in the number of headache days from baseline.

The nVNS device produces an electrical signal that delivers a low voltage current to stimulate the neck in the vicinity of the vagus nerve, an area implicated in migraine.

Past studies have demonstrated the efficacy of implanted VNS devices for patients with epilepsy or depression, but up until now only small case reports and studies have investigated the therapy for preventing migraine. "Despite the potential benefits of implanted VNS therapy, the high risks and costs of surgical implantation have hindered its clinical evaluation," wrote the authors of the study, led by Stephen D. Silberstein, MD, FAAN, professor of neurology and director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia.

The trial, known as the EVENT study, was conducted at six tertiary care headache centers between October 2012 and April 2012. For the study, investigators randomized 59 people with chronic migraine (defined as 15 or more headaches per month), ages 18 to 65, to the handheld nVNS device or a sham device for two months. Every day, patients self-administered two two-minute stimulations (at a low voltage electrical pulse) five to ten minutes apart at three pre-specified times a day. They recorded data on safety and tolerability, as well as the efficacy of the device as determined by the number of headache days per 28 days. Following the two-month randomized phase, patients received the nNVS treatment for six months.

At the end of the two months, the mean change of headache days from baseline was not statistically different between groups: The nVNS group reported a mean change of 1.4 fewer headaches, while the control group reported .02 fewer headaches from baseline — a non-significant difference. At eight months, however, 27 of the 59 participants who completed the trial had 7.9 fewer headache days — a significant mean change from baseline (p<0.01).

Study limitations included small sample size, blinding challenges, high discontinuation rate, and self-selection bias. The researchers are planning a larger, nine-month, open-label study to further investigate the effectiveness of the treatment.

Health officials in Florida reported that 14 cases of Zika virus were likely caused by the bites of local Aedes aegypt mosquitoes, according to the Centers for Disease Control and Prevention (CDC). In a telebriefing on August 1, the CDC said that at the request of Florida Governor Rick Scott, the federal agency had activated their Emergency Response Team to assist the Florida Department of Health (DOH) in their investigation, research, and sample collection efforts.

The cases, which were traced to a northern Miami community in Florida, are the first known reports of local mosquito-borne transmission in the United States. Officials believe the infection by the mosquito-borne virus might have occurred on or around June 15.

"All the evidence we have seen indicates that this is mosquito-borne transmission that occurred several weeks ago in several blocks in Miami," said CDC Director Tom Frieden, MD, MPH, in a news statement. "We continue to recommend that everyone in areas where Aedes aegypti mosquitoes are present—and especially pregnant women—take steps to avoid mosquito bites. We will continue to support Florida's efforts to investigate and respond to Zika and will reassess the situation and our recommendations on a daily basis."

The affected area stretches north from 20th street to 38th street and east of 5th Avenue in the Wynwood neighborhood of northern Miami. Federal health officials declined to specify whether the women were pregnant, according to the New York Times.

The Zika virus, which has been linked to cases of microcephaly, Guillain-Barre syndrome, and other neurological conditions, is spread to people primarily through the bite of an infected Aedes species mosquito. Pregnant women can pass the virus to their fetuses during pregnancy or birth. But Zika infections can also be transmitted to partners through sex, according to the CDC.

In response to the latest reports, the CDC issued a travel advisory to discourage pregnant women from visiting the North Miami neighborhood—the first such travel advisory for the Zika virus in the US.

Among instructions for pregnant women and their partners, the CDC said that men and women should take steps to prevent mosquito bites; that pregnant women and their partners should use condoms or other barriers to prevent infection every time they have sex; and that women "who live in or frequently travel to this area" should be tested for Zika in the first and second trimester of pregnancy. In addition, the CDC advised that couples trying to have a baby who traveled to this area should wait at least eight weeks before conceiving a pregnancy, and that men with symptoms of Zika virus disease should wait at least six months after symptoms begin to attempt conception.

All women who are pregnant in the United States should be tested for possible Zika virus exposure during every prenatal care visit, the CDC added.

In the August 1 telebriefing, Dr. Frieden said "aggressive mosquito control measures don't seem to be working as well as we would have liked. This may happen for at least one of three reasons. First, it's possible that the mosquitoes there are resistant to the insecticides that have been used. Second, it's possible that there are what we call cryptic breeding places or small amounts of standing water where mosquitoes continue to hatch. And third, it's possible simply that this is a very difficult mosquito to control, particularly in a complex urban environment like the one north of downtown Miami. "

To date, 1,658 cases of Zika have been reported to CDC in the continental United States and Hawaii. The CDC expects the number to rise. For updates on the Zika virus, visit http://www.cdc.gov/zika/.

Estradiol, an estrogen-containing hormone therapy, may not affect the cognitive abilities of healthy postmenopausal women, regardless of whether treatment begins within six years of — or ten or more years after — menopause, according to a study published in the July 15 online issue of Neurology.

During a mean treatment period of 57 months, 1 mg oral 17b-estradiol daily compared to placebo had no effect on cognitive composite change scores in either postmenopausal group, the research team at Stanford University and University of Southern California reported.

Earlier studies have proposed that the effects of hormonal therapy on cognition can vary by age or by timing in relation to menopause, but the results have been inconsistent, study authors wrote. But the so-called "timing hypothesis" — that estradiol benefits memory and thinking in women soon after but not later menopause — had not been addressed in a randomized trial in both younger and older postmenopausal women.

The Early vs Late Intervention Trial with Estradiol (ELITE) randomized 567 healthy women between the ages of 41 and 84 within six years of menopause or 10 years after menopause to oral 17b-estradiol 1 mg daily or placebo for an average of five years. All participants underwent cognitive tests of verbal memory, executive function, or global cognition: 567 women provided cognitive outcomes after 2.5 years; 455 women provided outcomes after five years.

The researchers found no significant differences in cognitive outcomes between the two groups of women. Compared to their baseline scores, both groups of women improved in verbal memory due to practice. Scores were the same for women with and without hot flashes, and for women who had a uterus and those who had a hysterectomy.

"This study fails to confirm the timing hypothesis," said the lead study author Victor W. Henderson, MD, FAAN, professor of health research & policy and of neurology & neurological sciences at Stanford University, in a news release. "Our results suggest that healthy women at all stages after menopause should not take estrogen to improve memory. At the same time, women need not particularly be concerned about negative effects of postmenopausal estrogen supplements on memory when used for less than five years."

But the study authors offered this caveat: "Results do not generalize to women of reproductive age or in the menopausal transition, to women with primary ovarian insufficiency or premature menopause induced by surgery or cancer chemotherapy."

They added that among limitations, "the study lacked power to exclude small treatment effects in participant subgroups. It was not designed to assess short- term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease."

Children who carry the apolipoprotein E (APOE) e2 and e4 genotypes showed differences in gray matter maturation and had worse performance on cognitive tests, according to a new study published online July 13 ahead of the print edition of Neurology.

Prior studies have evaluated the association between APOE genotypes and cognitive outcomes, but they assessed only groups of individuals with one or two genotypes – for instance, APOE e4 and APOE e2 – or specific cognitive outcomes, such as IQ and academic achievements. Researchers sought to study group differences across all six APOE genotypes in both gray matter changes and cognitive outcomes in children.

"This large sample of children validated and extended prior small studies that showed altered brain development in e4 carriers," the study's authors, led by Linda Chang, MD, professor of medicine and program director of neuroscience and MR research at the University of Hawaii, wrote. The findings suggest that "studying APOE polymorphism in young children may provide early indications of risk of future brain injuries and dementia."

Researchers evaluated 1,187 healthy children ranging in age from 3 to 20 years who had one of six APOE genotypes and were enrolled in the cross-sectional Pediatric Imaging Neurocognition and Genetics Study. They analyzed MRI scans to assess several aspects of gray matter changes, including morphometry and fractional anisotrophy. They also analyzed the study subjects' results on the NIH Toolbox Cognition Battery, which comprises seven tests that assess eight cognitive domains, including executive function, visual attention, episodic memory, and working memory.

They found that children with each variation of the e4 genotype – e2e4 and e4e4 – showed the greatest differences in gray matter maturation. Children with e2e4 had the smallest hippocampi; children with e4e4 had the lowest hippocampal fractional anisotrophy; and children with e4e4 showed age-dependent thinning of the entorhinal cortex.

They also found differences in cognitive function across ages. Younger children with the e2e4 genotype had larger parietal gyri, and younger children with the e4e4 genotype had thinner temporal and cingulate isthmus cortices or smaller hippocampi, which were associated with poorer performance on tests of attention and working memory in the NIH Toolbox.

The results, the study's authors wrote, show that "the e4e4 and e2e4 genotypes may negatively influence brain development and brain aging at the extremes of age."

The study's authors noted several limitations of the study, however. Among them, they noted that the "cohort effect" – in which individuals in a cohort share similar experiences because, for example, they are born around the same time and have similar environmental exposures – and the cross-sectional nature of the study may have biased the age-related brain measures, and that longitudinal follow-ups may be required to confirm the "true developmental trajectories" of children with e2 and e4 genotypes. They also noted that some children were not able to complete all the tests in the NIH Toolbox, and that the study sample could have been more ethnically diverse.

For up to five years after an initial stroke, stroke survivors had an increased risk of a recurrent stroke and of post-stroke dementia, according to a new study published online on July 14 in Stroke. Cardiovascular risk factors that existed before the first stroke were associated with a substantial number of recurrent strokes, and to a lesser extent with post-stroke dementia, researchers found.

Previous studies have established that recurrent stroke risk is strongly associated with cardiovascular risk factors at the time of the first stroke. But the researchers, led by Marileen L. P. Portegies, MD, professor of epidemiology and neurology at Erasmus University Medical Center in Rotterdam, Netherlands, wanted to investigate the association of recurrent stroke and post-stroke dementia with risk factors that existed before the first stroke.

"The main novelty of our study is that we showed that a substantial proportion of recurrent strokes and dementia cases after stroke is attributable to prestroke cardiovascular risk factors," the study's authors wrote. The findings emphasize "the need of optimizing both primary and secondary preventions" of cardiovascular disease, they concluded.

Between 1990 and 2012, researchers followed 1,237 participants who had a first-ever stroke in the population-based Rotterdam Study and matched them by sex, age, and other factors with 4,928 stroke-free participants. They found that the risk of recurrent stroke and post-stroke dementia was highest in the first year after the incident stroke. However, after that first year, patients had a threefold increased risk of recurrent stroke (incidence rate ratio: 3.16) and an almost twofold increased risk of post-stroke dementia (incidence rate ratio: 1.73) compared to stroke-fee people. The elevated risk remained statistically significant until the fifth year, researchers found.

These percentages were similar for first-ever stroke and dementia cases in the matched stroke-free population, researchers added.

The researchers noted that the known modifiable risk factors used in the study – including hypertension, high cholesterol, low HDL cholesterol, BMI of at least 25, and diabetes – only contributed to a part of recurrent stroke and post-stroke dementia cases. Further research into novel modifiable risk factors – including genetic factors, biomarkers, and response to treatment – may be necessary, they said.

The authors pointed out several study limitations. Among them were the lack of data on stroke severity – which they noted was a "possible mediator" in the association with recurrent stroke and post-stroke dementia risk – and that pre-stroke cardiovascular risk factors were only measured once.

TBI with loss of consciousness was associated with an increased risk for Lewy body accumulation (shown here).

Credit: Murat Gokden

BY SARAH OWENS

Traumatic brain injury (TBI) with a loss of consciousness (LOC) was associated with an increased risk later in life for Parkinson's disease, progression of parkinsonism, and accumulation of Lewy bodies, but not with dementia or Alzheimer's disease (AD), according to a review of data from three prospective cohort studies published online July 11 in JAMA Neurology.

The data from the three studies — which included the Religious Orders Study (ROS), Adult Changes in Thought (ACT) study, and the Memory and Aging Project (MAP)— included clinical outcomes and post-mortem neuropathological analyses.

"Several previous studies have suggested associations between TBI with LOC and AD," wrote the authors of the study, led by Paul K. Crane, MD, MPH, professor of medicine at the University of Washington in Seattle. "To our knowledge this study is by far the greatest ever on this topic. With more than adequate power to detect an association between TBI with LOC and AD, we found none. We found that TBI with LOC was associated with Lewy body accumulation, progression of parkinsonian features, and the risk for incident PD."

Researchers evaluated a total of 7,130 participants for a total of 45,190 person-years of follow-up. Of these participants, 865 reported a history of TBI with LOC. Researchers analyzed data for both clinical outcomes – including dementia, Alzheimer's disease, Parkinson's disease, parkinsonism, and mild cognitive impairment – and neuropathologic outcomes, including neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis.

The authors noted that the total autopsy sample size – 1,682 autopsies – was more than seven times that of a previous evaluation of associations between TBI and pathologic findings of Alzheimer's disease.

Among their findings, TBI with LOC was positively associated with incident Parkinson's disease in the ACT study (hazard ratio of 3.56 for a TBI with LOC lasting longer than one hour) and with progression of parkinsonism signs in the ROS and MAP (odds ratio of 2.23 for TBI lasting longer than one hour). They also found that TBI with LOC was associated with presence of Lewy bodies (relative risk of 2.64 for TBI with LOC lasting longer than one hour in the ACT study) and with cerebral microinfarcts (relative risk of 2.12 for TBI with LOC lasting longer than one hour in ROS and MAP).

However, no association was found between TBI with LOC and incident dementia (HR of 1.03 for TBI with LOC lasting one hour or less; HR of 1.18 for TBI with LOC lasting longer than one hour).

Researchers included the apolipoprotein genotype– associated with Alzheimer's disease risk – in their analysis, but they found it had a "negligible" effect on the results.

The authors pointed out several limitations in their analysis, however. Among them, they did not enroll ethnically diverse populations and there were systematic differences in research practices. They noted, too, the lack of available data to analyze associations between TBI with LOC and early-onset Alzheimer's disease.

Deutetrabenazine appeared to control chorea associated with Huntington's disease over the course of 12 weeks, according a study published July 5 in the Journal of the American Medical Association.

Chorea – an involuntary, sudden movement that can affect any muscle and can flow randomly across regions of the body – carries safety risks and can interfere with daily function. The Food and Drug Administration approved tetrabenazine in 2008 for treating Huntington's disease-associated chorea, but there have been concerns about tetrabenazine-associated adverse effects at peak concentration, including somnolence, depression, anxiety, and nausea.

Deutetrabenazine, which is structurally related to tetrabenazine, contains deuterium, a nontoxic form of hydrogen that offers the advantages of a longer half-life and reduced metabolic variability. Researchers hypothesized that these properties would allow less frequent and lower daily doses while reducing adverse treatment effects, resulting in an improved risk-benefit profile.

Researchers from the Huntington Study Group enrolled 90 ambulatory adults with manifest HD from 34 Huntington Disease Group investigational sites in the US and Canada . They randomized 45 participants to receive deutetrabenazine and 45 participants to receive placebo. Over the first eight weeks, participants were titrated to an optimal dosage level; dosage began at 6 mg daily, and increased by 6 mg daily each week until chorea was adequately controlled, the patient experienced a clinically significant adverse event, or the 48-mg maximum allowable dose was reached. Over the following four weeks, participants received a maintenance dose twice a day, followed by a one-week washout period.

The researchers' primary end point was a 2.7-unit difference in total maximal chorea score – a standardized assessment that measures the frequency and severity of chorea in seven body regions, with a range from 0 to 28; higher scores indicate worse chorea. They found that mean total maximal chorea scores in the deutetrabenazine group improved from 12.1 to 7.7, compared to an improvement from 13.2 to 11.3 in the placebo group, resulting in an average between-group difference of 2.5 units (p<0.001).

The findings indicate that deutetrabenazine treatment significantly improved chorea control as measured by the total maximal chorea score and by three other secondary end points, the researchers wrote. Although the observed 2.5-unit treatment effect fell short of the trial's 2.7-unit goal, the study authors nonetheless suggested that the findings may be of clinical relevance. They noted that the safety profile of deutetrabenazine was similar to that of placebo; neither drug showed worsening of depression, and rates of anxiety and parkinsonism were not significantly different between the two drugs.

The study authors noted a number of limitations. Among them, they cited the short duration of the trial and the fact that the study design did not allow for a detailed safety assessment. They noted, as well, that only a small proportion of participants were stratified based on prior exposure to tetrabenazine.

"Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety," they concluded.

In an accompanying editorial, Michael D. Geschwind, MD, PhD, FAAN, professor of neurology, and Nick Paras, PhD, associate adjunct professor of neurology, both of the University of California at San Francisco, said the study was well-done and clearly presented. But they added: "As the authors note, the minimally clinically important difference for the primary outcome of the change in total maximal chorea score has not been determined, so the clinical relevance of the findings is not definitive."

They pointed out, as well, that the trial did not directly compare the safety and efficacy of deutetrabenazine with tetrabenazine. "From a clinician's standpoint, an ideal trial might have had 3 groups comparing deutetrabenazine, tetrabenazine, and placebo," they wrote, adding that the short, 12-week trial duration meant that the "sustainability of benefit" remains an unknown. The editorialists note that an ongoing trial, the Alternatives for Reducing Chorea in Huntington Disease (ARC-HD) trial, may address some of these issues.

People who have type 2 diabetes mellitus (T2DM) and mild cognitive impairment (MCI) may experience accelerated cognitive decline, according to a study that was published online June 6 ahead of the print edition in Neurology. The acceleration may be due to the disease's effects on metabolism and brain volume, researchers said.

Previous studies have reported biological evidence for the association of T2DM with cognitive decline, the study authors noted. But the current analysis suggests that T2DM may play an additional role in that process by reducing whole brain volume and glucose metabolism.

"Although it is difficult to delineate the specific contributions of atrophic brain structural changes relative to changes in function represented by impaired glucose metabolism, both processes may be involved in cognitive decline in patients with T2DM and MCI," the study authors concluded.

The research team identified 159 people with T2DM from a cohort of 1,600 enrollees in the Alzheimer's Disease Neuroimaging Initiative — an ongoing study assessing imaging and other biomarkers of mild cognitive impairment and early Alzheimer's disease. They compared imaging data on six different groups: 398 healthy controls with no T2DM; 935 with mild cognitive impairment (MCI) with no T2DM; 189 with Alzheimer's disease (AD) but no T2DM; 31 healthy controls with T2DM; 99 with MCI and T2DM; and 14 with AD and T2DM.

The brain scans included both MRI images, which researchers used to measure brain volume and cortical thickness, and PET images, which they used to measure the uptake of [18F]-fluorodeoxyglucose (FDG) – a marker of glucose metabolism – in gray matter and white matter regions of the brain.

They found that whole brain volume and whole brain FDG were significantly different in those with T2DM. Participants with MCI and T2DM had a lower brain volume compared with participants who had MCI but no T2DM (p=0.009). And mean FDG uptake in gray matter and white matter was lower in patients with both MCI and T2DM than in those with MCI and no T2DM (p=0.04).

Three brain regions – the frontal lobe, the sensory motor cortex, and the striatum – had the greatest change in glucose metabolism for people with T2DM and MCI. However, "no volume change was detected in any subregion of the brain, so the effects of [T2DM] were only observed when considering the whole brain volume," the researchers wrote.

Brain volume or glucose metabolism did not appear to have a significant effect on two groups of healthy controls or the two groups of people with Alzheimer's disease. Additionally, researchers found that concurrent antidiabetic treatment did not affect measures of brain volume or metabolism.

The study authors noted the analysis was limited by the fact that the study was cross-sectional rather than longitudinal and therefore could not measure the acceleration of T2DM-associated cognitive decline over time. Additionally, the study did not examine the underlying mechanisms of cognitive decline, which researchers hope future fluid biomarker studies may help to explain. Finally, they noted that medical history was self-reported for participants with T2DM, which may have compromised the completeness or accuracy of the findings.

Oligomeric alpha-synuclein (AS) has emerged in recent years as a possible driver of Parkinson's disease (PD) pathogenesis, and mitochondrial dysfunction has long been thought to contribute as well. But a new study shows that oligomeric AS impairs mitochondrial transport and reduces respiration, revealing a previously unknown interaction between these two central players in the PD disease process, and pointing to a new therapeutic approach to the disease.

"This identifies a defined mechanism by which alpha-synuclein acts on mitochondria," said J. Timothy Greenamyre, MD, PhD, professor and vice-chair of neurology and director of the Pittsburgh Institute for Neurodegenerative Diseases at the University of Pittsburgh. "I think this mechanism is likely playing a central role in most forms of Parkinson's disease," Dr. Greenamyre, the lead author of the study published in the June 8 edition of Science Translational Medicine, said.

"For a long time, it has been recognized that there is a bidirectional interaction between alpha-synuclein and mitochondria," said Dr. Greenamyre. Increasing the level of AS causes mitochondrial impairment and an increase in reactive oxygen species (free radicals), while inhibition of mitochondrial electron transport causes accumulation of AS, but the mechanisms have been unclear.

While the mitochondrion contains its own genome, the vast majority of mitochondrial proteins are encoded in the nucleus, and tagged with a mitochondrial targeting signal (MTS) that promotes transport of the protein into the mitochondrion. The targeting signal binds to a receptor on the mitochondrial outer membrane, called TOM20. In some situations, AS can take on a conformation similar to that of the MTS, leading Dr. Greenamyre to hypothesize that AS might interfere with mitochondrial transport.​

To test that hypothesis, Dr. Greenamyre and colleagues used a "proximity ligation assay," a test of whether two proteins come close together. The technology extends the capabilities of traditional immunoassays to include direct detection of proteins, protein interactions, and modifications with high specificity and sensitivity. The advantage of the assay, Dr. Greenamyre said, is that it doesn't rely on transfecting cells with abnormal amounts of target proteins, which might introduce interactions that would not occur under normal conditions.

Dr. Greenamyre first tested the effects of rotenone, a plant-derived insecticide that inhibits mitochondrial complex I and is used as a model for PD. In rats treated with rotenone, the assay indicated a marked interaction between AS and TOM20 in nigrostriatal dopamine neurons, compared to untreated rats; this interaction also reduced import of a critical component of complex I. Similar results were obtained in tissue from PD substantia nigra, with an approximately 10-fold increase in the signal for AS-TOM20 interaction in PD tissue versus controls.

While aggregation of AS is the pathological hallmark of PD, the focus in recent years has been on the pathogenic effects of oligomers, with two or three or four AS monomers linked together. In non-rotenone treated cells, there was no interaction between monomeric AS and TOM20. But the oligomeric forms did bind with TOM20, as did AS pre-treated with dopamine —— which causes poorly characterized changes to the molecule — and a mutant form of AS that mimics phosphorylation.

In cell culture, Dr. Greenamyre found that while the addition of small amounts of monomeric AS had no effect on mitochondrial transport, the equivalent amount of oligomeric AS (the dopamine-treated form or the phosphomimic) reduced transport by half. This additional AS, Dr. Greenamyre noted, added no more than a few percent to the overall amount of AS in the cell.

"That suggests that you don't need a lot of alpha-synuclein to have a bad effect. You just need a little of the wrong type. It also suggests that anything that predisposes AS to post-translational modifications is also going to cause problems."

Those problems, he found, included a 30- to 40-percent decrease in respiration, an increase in oxidative species within the mitochondrion, and a 50 percent reduction in membrane potential. Overexpression of TOM20 ameliorated these harmful changes, presumably because the extra TOM20 bound up all the harmful species, allowing unbound TOM20 to do its job.

TOM20 normally interacts with another member of the transporter complex, TOM22, and that interaction was reduced by each of the modified AS species. However, Dr. Greenamyre found, that interaction was also markedly reduced in nigrostriatal dopamine neurons, even without oligomeric AS treatment.

"This suggests that dopamine neurons at baseline are already struggling with mitochondrial membrane transport," he said. "We were very surprised by this, but it may explain why dopamine neurons are so vulnerable to impairment." One possible explanation is that, within the cells, dopamine occasionally leaks from vesicles and induces the changes in AS that lead it to interact with TOM20.

Dr. Greenamyre noted that the interaction of AS and mitochondria can lead to a vicious circle, in which modification of AS can lead to impairment of membrane transport and reduced mitochondrial activity, which can lead to further oxidation and oligomerization of AS. If this model is correct, the process may begin in different ways in different patients, perhaps through genetically determined alterations in AS production or dopamine handling, or by environmentally induced dysfunctions in mitochondria. Both would eventually trigger the same self-reinforcing cascade.

"Therapeutically, there is probably no simple way forward," Dr. Greenamyre said, but he noted that even a small decrease in AS might have a beneficial effect, if it can restore the balance in favor of monomeric AS.

Look for more coverage of this study in the July 7, 2016 issue of Neurology Today.

More than one-third of patients with atrial fibrillation (AFib) who were at moderate-to-high risk of stroke were treated with aspirin alone in outpatient cardiac practices, despite guidelines that recommend the use of oral anticoagulants, according to a study published in the June 28 edition of the Journal of the American College of Cardiology.

AFib patients who were treated with aspirin alone tended to be younger, had a lower body mass index, were more likely to be female, and were more likely to have comorbidities, including diabetes, hypertension, high cholesterol, and peripheral artery disease.

Cardiovascular specialists may prescribe aspirin instead of oral anticoagulants because they have "the misperception that aspirin exhibits adequate efficacy compared to oral anticoagulants," said Jonathan C. Hsu, MD, the lead study author and assistant clinical professor of medicine, cardiology and cardiac electrophysiology at the University of California, San Diego, in a news release accompanying the study.

He noted that men had a 6 percent greater likelihood of being prescribed anticoagulants despite the fact that women have an increased risk of stroke.

As part of their analysis, the researchers culled data from the National Cardiovascular Data Registry (NCDR)'s Practice Innovation and Clinical Excellence (PINNACLE), a prospective national registry of cardiovascular care in the United States. They restricted the study cohort to patients who had a moderate-to-high risk of thromboembolism, identified by a CHADS2 score of 2 or greater. (On the CHADS2 scale, patients are assigned 1 point each for congestive heart failure, hypertension, age of at least 75 years, and diabetes; and 2 points for having had a stroke or a transient ischemic attack.)

The researchers found that 38.2 percent of 210,380 (or 80,371) patients in the study were treated with aspirin alone, while 61.8 percent (130,009) were treated with anticoagulants (warfarin or non-vitamin K antagonist oral anticoagulants). Comorbid conditions were the strongest predictive factors of aspirin use over oral anticoagulation use.

The study authors noted several study limitations. Among them, the study lacked follow-up data on outcomes — subsequent strokes or bleeding, for example — from those in the PINNACLE registry, and the registry enrolled only patients from cardiology practices that were dedicated to quality improvement, so the data may not be generalizable to other practices in the US. In addition, they noted that the PINNACLE registry did not capture data on bleeding risk, which may have provided insight on prescription preferences.

In an accompanying editorial, Sanjay Deshpande, MD, medical director of cardiac electrophysiology, and L. Samuel Wann, MD, cardiologist, both at Columbia St. Mary's Hospital in Milwaukee, WI, said the study provided valuable insight into prescribing practices, adding that it raises a larger issue about physicians' duty to adhere to guidelines.

While they noted that guidelines are meant to be recommendations, not dictates, and that clinicians may – and even should – adapt them to suit patients' individual needs, they said, "It is nonetheless concerning that the highly motivated, conscientious, and talented cardiologists working in quality-conscious institutions that contribute their data to the NCDR are not prescribing anticoagulation in one-third of their qualifying patients."

The consequences of not adhering to treatment guidelines for high-stroke-risk AFib patients – which may include intracerebral hemorrhage – can be devastating. "'Take 2 aspirin and call me in the morning' is not appropriate treatment for a patient with atrial fibrillation at risk for thromboembolism," they concluded.

A 66-year-old man seeking out treatments for residual deficits from an ischemic stroke at stem cell clinics in China, Argentina, and Mexico returned to the US with far more serious complications than he had before, according to correspondence published in the June 22 issue of the New England Journal of Medicine.

Among the adverse events, the man had progressive lower back pain, paraplegia, and urinary incontinence, and an MRI revealed a lesion in his thoracic spinal cord and thecal sac. Subsequent analysis revealed that he had a densely cellular, proliferative neoplasm with glial differentiation on his spine.

The case underscores the dangers of stem cell tourism and the serious complications that can occur when patients receive proliferating stem cells from unregulated stem cell clinics outside of clinical trials.

"The unregulated commercial stem-cell industry is not only potentially harmful to individual patients but also undermines attempts to study stem-cell therapies in clinical trials," wrote Aaron Berkowitz, MD, PhD, Michael B. Miller, MD, PhD, and seven other physicians at Brigham and Women's Hospital in Boston, MA. The case supports the need for more investigations of commercial stem-cell clinics and increased patient education about the risks of stem-cell tourism, they added.

Of particular note in the case is that histopathological and molecular analyses showed that the glioproliferative lesion appeared to have originated from the intrathecally introduced exogenous stem cells. The lesion, the letter's authors said, had a number of features that resembled malignant gliomas, including nuclear atypia, a high proliferation index, and glial differentiation, but did not show other features typical of cancer. Thus, they noted, the lesion could be considered a new growth, but it could not be assigned to any category of previously described human neoplasm on the basis of the data they gathered.

Embryonic and other stem cells have tumorigenic potential, the authors of the letter noted. When stem cells divide rapidly in culture, they can acquire dangerous mutations that may make cells prone to malignant transformation, they wrote, and that is why experimental treatments must be studied in a safe, regulated environment.

The size and location of hematoma after intracerebral hemorrhage (ICH) are associated with the risk for early development of dementia (within six months), but not with delayed dementia (after six months), according to a new study published online ahead of print on June 13 in JAMA Neurology.

Patients who have had an ICH experience high rates of cognitive impairment, but until now, few studies have examined risk factors to explain the association. The findings suggest that different biological mechanisms account for early versus delayed cognitive decline after ICH.

The study, led by Alessandro Biffi, MD, a behavioral neurology and neuropsychiatry fellow at Massachusetts General Hospital, was the first comprehensive longitudinal study of cognitive impairment after intracerebral hemorrhage, wrote the authors. "Prior studies reported high rates of dementia after ICH but were unable to fully describe its predictors… We demonstrated [that] there was a significant discrepancy in risk factor profiles between risks for [early post-ICH dementia] and those for [delayed post-ICH dementia.]"

The researchers enrolled 738 patients at Massachusetts General Hospital between January 2006 and December 2013 who had survived for at least three months after an ICH and did not have dementia. Researchers followed up with patients at three and six months after the initial ICH and every six months thereafter. They then administered a modified Telephone Interview for Cognitive Status (TICS-m), a telephone-based assessment tool that measures cognitive performance on a scale from 0 to 39, where the upper scores mean better cognitive performance. The researchers also reviewed the patients' electronic medical records to determine their cognitive status.

They found that 279 (37.8 percent) of patients who experienced ICH developed dementia during the follow-up period: 140 developed incident dementia within six months, and 139 developed dementia after six months. Using imaging data, researchers determined that the lobar location of the hemorrhage (hazard ratio: 2.04; p=0.02 for heterogeneity) and the volume of the hemorrhage (hazard ratio: 1.47 per 10-mL increase; p<0.001 for heterogeneity) were both associated with the early development of post-ICH dementia. However, they did not find a similar association with the development of dementia after six months.

Several other risk factors were associated with the risk of delayed post-ICH dementia — including educational level (p<0.001 for heterogeneity), diagnosis of a mood disorder (p=0.01 for heterogeneity), and the severity of white matter disease (p=0.04 for heterogeneity). Overall, of all identified risk factors, only advancing age at index ICH represented a shared risk factor for early and delayed post-ICH dementia.

The findings, researchers said, support the hypothesis that different mechanisms underlie cognitive impairment after ICH depending on the size and location of hematoma.

In an accompanying editorial, Rebecca F. Gottesman, MD, PhD, associate professor of neurology at Johns Hopkins University, wrote that the study is clinically significant, since the findings suggest that "it may be helpful to routinely incorporate questions about cognitive status and functional recovery after ICH." However, she noted that "it is not clear if, in the case of ICH, the hemorrhage is a symptom of an ongoing condition." Given this uncertainty, she wrote, "it may be important to consider dementia after ICH as both a potential cause and effect."

Researchers acknowledged the difficulty of separating the effect on cognitive outcomes of the acute bleeding event versus potential underlying disease processes, adding that future studies may help illuminate the pathophysiological factors of long-term cognitive decline after ICH. They also noted several limitations of the study, including the fact that they obtained information about cognitive outcomes from telephone-based, rather than in-person, evaluations; a lack of diversity in the study cohort; and their inability to capture the precise timing of dementia onset.

Women who experience migraine may have up to a 50 percent increased risk for major cardiovascular disease and an increased risk of death, according to the results of a study published online ahead of print on May 31 in the British Medical Journal. The findings, gathered over more than twenty years from a large cohort of women, suggest that migraine "should be considered an important risk marker for cardiovascular disease" in women, the study authors said.

The findings corroborate the results of other population-based cohort studies that associate migraine with an increased risk for cardiovascular disease, the study authors wrote.

"Although most studies link migraine with aura with increased risk of ischemic stroke, emerging evidence indicates that this risk extends to other cardiovascular disease as well," wrote the authors of the study, which was led by Tobias Kurth, PhD, professor of public health and epidemiology and director of the Institut of Public Health, Charité – Universitätsmedizin Berlin, Germany. "Our data support consideration of a history of migraine as a marker for increased risk of any cardiovascular event."

For the Nurses Health Study II trial, researchers followed 115,541 registered female nurses ranging from 25 to 41 years in age from 1989 to 2011. At a baseline assessment in 1989, 17,531 women (15.2 percent) indicated that they had been diagnosed with migraine by a physician. Every two years, the study participants reported any incident cardiovascular disease event on a follow-up questionnaire; self-reported information was confirmed by a physician, who was blinded to the research.

A total of 1,329 major cardiovascular disease events and 223 deaths occurred during the study period. Researchers found that women with migraine had a higher risk of all evaluated individual outcomes of cardiovascular disease compared to women without migraine. Overall, women with a diagnosis of migraine had a 50 percent increased risk of stroke, myocardial infarction, or other major cardiovascular disease compared to controls without migraine, corresponding to a hazard ratio of 1.50. The highest risk estimates for individual cardiovascular outcomes were for stroke (with a hazard ratio of 1.62) and angina/coronary revascularizations (with a hazard ratio of 1.73). Women with migraine also had an increased risk of cardiovascular mortality (with a hazard ratio of 1.37).

These associations were "similar" across subgroups of women, the study's authors wrote, with no significant differences in associations based on age, smoking status, hypertension, and use of oral contraceptives or postmenopausal hormones.

The study authors noted several limitations. Among them, they said self-reported physician diagnosis of migraine may have led to misclassification, and that "no information on frequency of migraine or migraine specific information was available." They also noted that the link between migraine and cardiovascular disease so far has no clear explanation, and that no data exist that show whether prevention of migraine can help reduce the risk of cardiovascular disease.

In an editorial accompanying the study, Rebecca Burch, MD, instructor in neurology at Harvard Medical School, and Melissa Rayhill, MD, assistant professor of neurology at the State University of New York at Buffalo, agreed that migraine should be considered as an early life marker for later cardiovascular risk. However, they cautioned that the "magnitude of the risk should not be over-emphasized," noting that the risk "is small at the level of the individual patient," but "still important at a population level because migraine is so prevalent."

Brain abnormalities detected on diffusion tensor imaging (DTI), a magnetic resonance imaging technique, helped predict the recovery outcomes of patients with mild traumatic brain injury (mTBI) one year later, according to a new study published online ahead of print on June 9 in The American Journal of Neuroradiology.

For the study, emergency department physicians at Montefiore Medical Center performed DTI scans of 39 patients diagnosed with mTBI within 16 days of the injury, as well as healthy controls. The researchers found that the scans of those with mTBI, compared with controls, showed two distinct types of white matter damage: areas of abnormally high fractional anisotropy (FA) — the uniformity of water molecules detected on DTI — or abnormally low FA.

Follow-up assessments with 26 patients one year later found that those whose DTI scans showed abnormally high FA had better outcomes on tests of cognition and post-concussion symptoms. Study subjects who had high FA in the left frontal lobe and left temporal lobe performed better on tests of attention and those who had high FA in the right thalamus experienced fewer emotional post-concussion symptoms, for example.

These outcomes, the study authors concluded, suggest that DTI imaging analyses of high FA in specific brain areas may be a good predictor of functional outcomes at one year after mild TBI.

"While we still lack effective treatments, we now have a better understanding of the neurological mechanisms that underlie a favorable response to concussion," said study leader Michael L. Lipton, MD, PhD, professor of radiology, of psychiatry and behavioral sciences, and of neuroscience at Albert Einstein College of Medicine, in a press release accompanying the study. "[This] opens a new window on how to look at therapies and to measure their effectiveness."

Noting that previous imaging studies of outcomes after mTBI did not have the ability to recognize spatial variation in the location of the injury — a principal feature of mild TBI — researchers used an individualized approach to assess the spatial heterogeneity of traumatic axonal injury in the study participants, called the Enhanced Z score Microstructural Assessment of Pathology, or EZ-MAP. The EZ-MAP, unlike other tools that measure damage caused by TBI, can delineate abnormal brain regions that relate to particular cognitive functions in individual patients.

The researchers noted that more studies are needed to validate the approach. "While were able to predict the outcomes for the patients in our study, more refined approaches — incorporating additional patient and injury characteristics, for example — may be needed when applying the test on widely differing individuals," Dr. Lipton said.

Therapies that lower blood pressure to below 140 mm Hg for patients with intracerebral hemorrhage may not be clinically necessary, according to a study that was published online June 8 ahead of the print edition in the New England Journal of Medicine.

In the new analysis, researchers compared outcomes — death and disability — from intensive treatment to lower blood pressure to a target of 110 to 139 mm Hg with those for patients whose blood pressure was lowered to a target of 140 to 179 mm Hg. Patients with lower blood pressure targets did not experience significantly different rates of death and disability, they found.

The standard blood pressure reduction target may be sufficient for controlling intracerebral hemorrhage, said Adnan Qureshi, MD, the lead author of the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial, in a news release accompanying the study. "Rapidly lowering blood pressure to normal levels may further damage the brain," Dr. Qureshi, professor of neurology, neurosurgery and radiology at the University of Minnesota, said, adding that the results will "help patients and their doctors make better treatment decisions."

The ATACH-2 investigators randomized 1,000 patients — who had a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition), and an average systolic blood pressure of 200.6 mm Hg at baseline — to intensive treatment that lowered blood pressure to 110 to 139 mm Hg or standard treatment that lowered blood pressure to 140 to 179 mm Hg. The study participants were given nicardipine, a blood pressure-lowering medication, within 4.5 hours after symptom onset.

At 90 days, 186 (38.7 percent) of the people in the intensive-treatment group died or had major disability compared with 181 (37.7 percent) in the standard-treatment group. Additionally, 55 (11 percent) of participants in the intensive-treatment group experienced neurologic deterioration within 24 hours, compared with 40 participants (8 percent) in the standard-treatment group.

"The absolute difference between the two groups in the rate of death or disability was one percentage point," wrote the study authors, which fell far short of the 10 points that would be significant enough to merit "broad acceptance of a new intervention."

The study authors compared the results of the ATACH-2 trial to those of INTERACT2, another trial that similarly measured the efficacy of treatments to lower blood pressure for patients with intracerebral hemorrhage. The INTERACT2 trial found that "the rate of death or disability… was nonsignificantly lower" for patients who were randomized to two treatment groups: one that lowered blood pressure to less than 180 mm Hg, and one that lowered blood pressure to less than 140 mm Hg. The results were published in the New England Journal of Medicinein 2013.

The ATACH-2 investigators hypothesized that "a more rapid intensive reduction" in blood pressure than was employed in the INTERACT2 trial might more successfully lower rates of death and disability, but they pointed out that their results did not confirm the hypothesis.

The study authors noted a number of trial limitations. For example, they said the use of intravenous antihypertensive agents prior to randomization — intended to ensure timely compliance with existing guidelines for lowering blood pressure in patients with acute intracerebral hemorrhage — may have "obscured the effectiveness of the trial intervention." They also pointed out that 56 percent of patients had a baseline GCS score of 15 at baseline, indicating "favorable characteristics," which may have "conferred a predisposition to a favorable outcome in our trial sample regardless of treatment (ceiling effect)." Finally, they noted that the "standardizing intensity of medical care provided at each [trial] site" may have influenced the results.

SAN DIEGO—The yawning, fatigue, photophobia, hunger, and other symptoms of the premonitory phase of migraine are providing important new clues to the disorder's underlying pathophysiology and potential new drug targets, according to a plenary presentation here on Saturday at the annual meeting of the American Headache Society.

"The beauty of being able to explore the biology of just yawning is that it allows us to dig down into role of dopamine," said Peter Goadsby, MD, PhD, professor of neurology and director of the headache clinic at the University of California, San Francisco. "Asking why people get hungry brings us to the role of the hypothalamus and of neuropeptide Y. We're learning about this. We can now link what the patients are telling us with the underlying biology."

Rather than seeing such symptoms as being caused by "triggers" in the external environment, Dr. Goadsby emphasized that they are beginning to understand that they may be generated internally by changes in the brain state, and are as much a part of the migraine as is the headache itself.

"There's all sorts of nonsense these days about diets that can supposedly prevent migraine," Dr. Goadsby said. "There are people who will eat only potatoes because they're told this will not cause migraine. Think of the number of children whose lives would be made wonderful by telling them cheese does not cause migraine."

On the role of dopamine, he cited a 2007 study he coauthored in the Annals of Neurology showing that central dopamine-containing neurons play a role in modulating trigeminovascular nociception. A more recent study by the research team, published in 2011 in Pain, found that serotonergic and dopaminergic antinociceptive pathways act simultaneously on neurons in the trigeminocervical complex, and that both need to be functioning for trigeminal sensitization to be reversed.

Dr. Goadsby and colleagues published one of the very few functional neuroimaging studies on the premonitory phase in the journal Brain in 2014. They gave nitroglycerin to patients with episodic migraine without aura who habitually experienced premonitory symptoms during spontaneous attacks. Through positron emission tomography scans, they could see that the nitroglycerin-initiated premonitory symptoms activated the posterolateral hypothalamus, which, he concluded, "can explain many of the premonitory symptoms."

"We were able to show that these changes in the hypothalamus are not a response to pain, but precede it," Dr. Goadsby said.

Given the previously known effect of neuropeptide Y on the autonomic nervous system, Dr. Goadsby described a paper in press in the journal Pain in which he and colleagues found that it inhibits trigeminovascular nociception in a dose-dependent manner.

"We think the Y1 receptor is the most important one," he told the audience. "We're pretty confident that neuropeptide Y in the hypothalamus has a big effect on these premonitory symptoms of craving and changes in hunger."

Turning to another peptide, he described research into the role of pituitary adenylate cyclase activating peptide (PACAP), a known trigger of migraines that has been shown to rise in migraine without aura and to normalize with sumatriptan.

"It's a very interesting peptide that works in the trigeminal system," Dr. Goadsby said. "The PACAP hypothesis is where the CGRP hypothesis was in the 1990s.

"So here's another whole system that helps you understand something a patient will tell you about on Monday, and leads to another target," Dr. Goadsby concluded. "There's so much work to be done. Just pick one of these premonitory symptoms and run down the biology of it."

Andrew Charles, MD, professor of neurology and director of the UCLA Goldberg Migraine Program at the David Geffen School of Medicine, said he shares Dr. Goadsby's view that headache is only one component of a migraine.

"If we can recognize mechanisms in the premonitory phase, there's a better chance we can shut them off before the train is out of the station," Dr. Charles said.

The hypothalamus, Dr. Charles added, offers what he called "an exciting new potential therapeutic target. The imaging studies by Dr. Goadsby of the premonitory phase really highlights changes in the hypothalamus. That would explain a number of the symptoms, like fatigue, changes in appetite, excessive urination. The peptides released by the hypothalamus might well be novel targets for therapy."

When it comes to risk factors that have an effect on the global burden of stroke, the news is mixed. Air pollution accounts for approximately 29.2 percent of the total global stroke burden worldwide, particularly in developing nations. But as much as 90 percent of stroke burden is attributed to "modifiable" lifestyle behaviors related to smoking, poor diet, and high blood pressure, according to the results of a new study published in the June 9 online edition of The Lancet Neurology.

Achieving control of these metabolic and behavioral risk factors could avert more than three-quarters of the stroke burden, the study authors said.

National governments and international agencies can work toward developing and prioritizing public health programs and policies to address these issues, said the lead study author Valery L Feigin, MD, FAAN, professor of epidemiology and neurology at the Auckland University of Technology in New Zealand, in a news release accompanying the study. And government leaders can use the powers of legislation and taxation to limit use of tobacco and consumption of alcohol, salt, sugar, and other foods associated with risk factors for stroke.

"All it takes is recognition of the urgent need to improve primary prevention, and the good will of the governments to act," Dr. Feigin said.

The study, led by contributors to the Global Burden of Diseases, Injuries, and Risk Factors Study 2013 and the Stroke Experts Writing Group, culled data from the 2013 Global Burden of Disease (GBD) study. That study group assessed and compared 79 risk factors or clusters of risk factors for stroke on a global, regional, and national level from 1990 to 2013. Researchers focused on the number of stroke-related disability-adjusted life-years, or DALYs, a comprehensive measure of population health.

The five leading risk factors for DALYs were high blood pressure, a diet low in fruits, a high body-mass index, a high-sodium diet, and smoking status.

The higher stroke burden for low-income countries compared to high-income countries held true for risk factors other than air pollution, as well. Most risk factors had the greatest effect on DALYs in low-income and middle-income countries, the study authors reported.

The researchers noted that the study had several limitations. Among them, they said, because of the lack of relevant epidemiological data from most countries, they were unable to include such major stroke risk factors as atrial fibrillation and substance abuse and predisposition to illnesses in these analyses.

Nonetheless, in a commentary accompanying the study, the editorialists stressed the importance of the findings. "Valery Feigin and colleagues provide persuasive evidence from their systematic analysis that stroke is largely preventable," wrote Vladimir Hachinski, MD, FAAN, professor of neurology at the University of Western Ontario, and Mahmoud Reza Azarpazhooh, MD, associate professor of neurology at Mashhad University of Medical Sciences in Mashhad, Iran. The study "provides a firm basis for policy makers to implement preventative measures. Moreover, the results will be important to update and monitor the epidemiology of stroke worldwide," they wrote.

The ability to measure amyloid and, more recently, tau in the living brain is helping researchers to better understand when the classic neuropathology of Alzheimer's disease (AD) develops and how it relates to the clinical signs of the neurodegenerative disorder.

A new study published in the May 11 issue of Science Translational Medicine and several other recent papers found that positron emission tomography (PET) using tau ligands track more closely with a patient's clinical signs, even milder ones, than do the results from PET imaging using amyloid-beta (Abeta) tracers. The findings suggest that PET tau biomarkers may be more useful than PET amyloid biomarkers in tracking the clinical progression to AD.

Beau Ances, MD, PhD, associate professor of neurology at Washington University in Saint Louis, MO, and senior author of the study, said that the addition of tau biomarkers will also be invaluable in developing and testing AD treatments designed to target the accumulation of toxic forms of the tau protein.

"These read-outs will be critically important in figuring out what tips the patient towards developing clinical signs that are responsible for progressive cognitive decline in AD," he said.

The Washington University scientists looked at specific regions of interest and correlated the brain scan findings to measures of these proteins in the cerebrospinal fluid (CSF) and to findings from neuropsychological tests.​

The scientists recruited 46 people and administered the clinical dementia rating (CDR) scale to obtain global cognitive and functional performance. They also asked the study subjects to complete pen-and-paper tests to assess their cognitive fitness. Then, each one of the study subjects had a PET scan done using either a T807 ligand (for tau) or florbetapir (for Abeta), and a magnetic resonance imaging scan. A subset of the participants also agreed to have a lumbar puncture done to obtain CSF to test levels of tau and Abeta.

The research team wanted to know whether the topographies mapped out using the PET scans related to the clinical status of people with mild AD and the healthy controls at the time of the neuropsychological testing. Earlier work from autopsy studies suggested that tau would be a stronger predictor of cognition decline than Abeta. But what would tests using these new PET agents find in living people?

The scientists measured 42 bilateral anatomical brain regions and split the group into two, depending on the presence of cognitive impairment based on the CDR. There were 36 cognitively normal people and ten with mild AD. The scans and the CSF measures showed that cognitively healthy participants had minimal tau tracer throughout the brain. (They did see tracer uptake in the basal ganglia, but this may represent "off-target" binding of this agent to neuromelanin, said Dr. Ances.)

Conversely, the 10 people with mild symptoms showed increased tau tracer uptake in the temporal lobes and throughout the cerebral cortex. Not surprisingly, these ten patients also had an accumulation of Abeta, although the protein was not in the same topographical areas.

The topographies were distinct — the tau topography was strongly localized in the entorhinal cortex, the inferior temporal cortex, and the cuneus — and Abeta was strongly localized in the frontal and parietal regions. There were correlations between the two biomarkers, which is not surprising because pathology studies have found that they must both be present in the brain for clinical signs to develop. Dr. Ances said that the spread of tau pathology to these areas was dependent on initial Abeta accumulation.

Abeta is present throughout the brain, even in cognitively normal individuals, according to this study and others. In contrast, cognitively normal individuals primarily have tau deposition in the medial temporal lobe.

"Changes were seen in the certain topography for amyloid, even in cognitively normal individuals," said Dr. Ances. "The regions that had amyloid deposition were distinct from the regions that had increases in tau deposition, but were nonetheless related," he said. "The regions that had increases in amyloid were strongly correlated with the regions identified as having an increase in tau, specifically temporal lobe structures. These results suggest that a series of regions that have an increase in amyloid are associated with a distinct set of regions that have tau pathology."

The scientists also were interested in correlating other known biomarkers with this novel tau PET imaging agent. They noted that elevated CSF tau was strongly predictive of tau deposition in the inferior temporal lobe. This same area was also associated with performance on pen-and-pencil tests that assessed naming of objects and animals (semantic memory) and performing a letter number sequence (visual spatial performance).

The neuropsychological testing was factored into the analysis of the regions of interest, and that is when they saw that PET tau, specifically in the inferior temporal lobe, was more closely related to global cognitive performance than Abeta.

"The tau deposition in this region was a better predictor of global cognitive performance," said Dr. Ances. Other recent studies have also shown that correlations between specific regional PET tau deposition and cognitive performance in certain domains. For example, worse performance on memory and language tests correlated with increased tau deposition in the medial temporal lobe.

"We are now able to see the location of where the changes take place in Alzheimer's disease," said Dr. Ances. He noted that the study showed that people can tolerate accumulation of tau in transentorhinal areas that is often seen with normal aging. However, once tau spreads to entorhinal and cortical areas — especially inferior temporal, parietal, and occipital lobes — individuals begin to develop clinical signs.

"We suspect that it is the combination of both widespread amyloid deposition and tau deposition in these regions that tips the patient from being asymptomatic to mild cognitive impairment," Dr. Ances said.

The investigators also analyzed the results from CSF tau and CSF Abeta and found that the cognitively normal healthy controls showed no evidence of abnormal tau or amyloid levels in the CSF. By contrast, cognitively normal individuals with preclinical AD had Abeta deposition on PET imaging and decreased Abeta in the CSF. Those with signs characteristic of mild AD had evidence of decreased CSF Abeta and increased CSF tau.

Dr. Ances and colleagues are hoping that the use of these imaging biomarkers will help clinicians diagnose and treat the disease at earlier stages. "Even delaying the onset of clinical symptoms by five to ten years would be extremely helpful," he said, noting that several prevention studies are now adding PET tau into their research designs to track the disease process.

For now, the Food and Drug Administration (FDA) has not approved PET tau for use outside of the research setting. But experts say it is only a matter of time. Three Abeta PET ligands have been approved since 2012 for clinical use; however, they typically are not covered by insurance. The Centers for Medicare and Medicaid Services is sponsoring a study — Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) — to assess whether the use of PET Abeta scans would lead to better health outcomes. The clinical use of scans has generated a lot of debate because there are no treatments to slow the disease process.

Look for more coverage of this study in the June 9, 2016 issue of Neurology Today.

Ticagrelor, a new antiplatelet agent, may not be superior to aspirin at reducing the risk of stroke, myocardial infarction, or death over a period of 90 days in patients who have experienced acute cerebral ischemia, according to a study published in the May 10 online edition of the New England Journal of Medicine.

Noting that aspirin offers limited benefit in the secondary prevention of ischemic stroke, researchers hypothesized that "more intensive antiplatelet therapy through a different mechanism of action may be more effective." Ticagrelor reversibly binds and inhibits the P2Y12 receptor on platelets and is direct-acting.

Led by Claiborne Johnston, MD, FAAN, dean of the Dell Medical School at the University of Texas at Austin, the SOCRATES (Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes) trial was designed to compare the effectiveness of ticagrelor with aspirin in reducing the rate of stroke, myocardial infarction, or death over a period of 90 days.

The researchers enrolled 13,199 patients in 674 centers in 33 countries who had a "nonsevere ischemic stroke or high-risk transient ischemic attack," which was not considered to be cardioembolic in cause, and for which they did not receive IV or intra-arterial thrombolysis. Study participants were randomly assigned to double-blind treatment with either ticagrelor or aspirin in a 1:1 ratio. Treatment began within 24 hours of diagnosis and continued for 90 days.

Researchers found that during 90 days of treatment, 442 of the 6,589 patients (6.7 percent) treated with ticagrelor experienced the primary endpoint – stroke, myocardial infarction, or death – compared to 497 of the 6,610 patients (7.5 percent) treated with aspirin. The results were not statistically significant, the study authors noted.

Despite the negative results on the primary outcome, Dr. Johnston and his co-investigators noted that there were some signals within subgroups suggesting that further study of ticagrelor could be warranted. In particular, they found no signs of increased hemorrhage or other safety issues in the ticagrelor arm of the study. Major bleeding occurred in 0.5 percent of patients treated with ticagrelor and in 0.6 percent of patients treated with aspirin; intracranial hemorrhage occurred in 0.2 percent and 0.3 percent, respectively, and fatal bleeding in 0.1 percent and 0.1 percent.

Notably, the study's authors found that there was a high risk of stroke in the first two weeks after an acute ischemic attack, with particularly high event rates in the first two days. This finding, the study's authors say, contradicts "some studies [that] have suggested that the risk of stroke after transient ischemic attack has decreased in recent years."

The study's authors cited several limitations of their study. They noted that while the trial aimed to test monotherapy ticagelor and aspirin, approximately one-third of the patients were taking aspirin at the time of the qualifying event, and since the antiplatelet effects of aspirin typically last several days, the individuals randomized to ticagrelor were essentially receiving dual antiplatelet therapy for the first few days. The study authors also noted that they had limited enrollment to patients who were at especially high risk for stroke, so these patients may have already undergone vascular interventions or other treatments. Finally, the study authors pointed out that the primary end-points of transient ischemic attack (TIA) were lower than expected, so it was possible that some of the enrolled patients had nonischemic conditions that mimicked a TIA.

Look for expanded discussion and commentary on the trial in the June 9 issue of Neurology Today.

Citing a number of "unmet needs" in rehabilitative stroke care, a new guideline from the American Heart Association and the American Stroke Association said the best evidence supports offering stroke patients these among other services: a formal fall prevention program during hospitalization, a balance training program, assessments for calcium and vitamin D supplementation for stroke survivors living in long-term care facilities, and speech and language therapy for individuals with aphasia.

The impetus for the evidence-based guideline, which was published online May 4 ahead of the June print issue of Stroke, was a "lack of clear guidelines regarding the efficacy of various interventions," guideline author Joel Stein, MD, Simon Baruch professor and chair of the department of rehabilitation and regenerative medicine at Columbia University College of Physicians and Surgeons, professor and chief of the division of rehabilitation medicine at Weill Cornell Medical College, and physiatrist-in-chief at New York-Presbyterian Hospital, told Neurology Today. A comprehensive guideline is particularly necessary because of the increasing array of therapeutic interventions for stroke, Dr. Stein said.

One of the guideline's most important new recommendations is that patients who have residual deficits after a stroke should receive a functional assessment from a clinician with expertise in rehabilitation, Dr. Stein said. Currently, "some people who have a stroke are not necessarily evaluated by an expert, especially if their symptoms are relatively mild. This can lead to rehabilitation at a lesser level of intensity than is appropriate, or for not as long as required, or that is not as focused on their specific needs as they deserve."

The guideline authors pointed out that stroke care in the US has become very heterogeneous, and is best when delivered by a multidisciplinary team that includes stroke neurologists, physiatrists, nurses, physical and occupational therapies, speech-language pathologists, as well as psychologists, nutritionists, social workers, and others.

The panel conducted computerized searches of available medical literature, including systematic reviews through 2014, and organized data and studies using the joint American Heart Association/American College of Cardiology classification system — dividing findings by level of certainty, the class of each trial, and the level of evidence.

It found that between 1996 and 2003 the proportion of patients who had not been referred for any post-acute rehabilitation increased from 26 to 31 percent. One analysis of 2006 Medicare data found the level had increased to 42 percent.

The guideline authors noted that stroke "has been managed medically as a temporary or transient condition," and that a comprehensive approach was needed to ensure a continuum of care, including social reintegration, health-related quality of life, and self-efficacy.

Dr. Stein also stressed the importance – noted for the first time in this guideline – of recognizing post-stroke depression. "It's extraordinarily common after a stroke – estimates range up to 40 percent for people who have significant depression after stroke. And there's an attitude that [depression] is an unavoidable consequence of stroke. That's very unfortunate, because, in fact, it's very disabling to be depressed; people withdraw socially, they are less active, and their mobility deteriorates. But this type of depression responds well to standard treatments for depression."

The guideline also includes an analysis of inpatient and outpatient rehabilitation treatment; in particular, it emphasizes the importance of impatient rehabilitation for patients with significant deficits. "This guideline, for the first time, clearly states that patients who qualify for inpatient rehabilitation facility care, which is high-level hospital rehabilitation, and who have access to it, really should receive that type of care in preference to lower levels of rehabilitation," said Dr. Stein. Inpatient rehabilitation offers the added benefit that it "supports strong teamwork among caregivers," Dr. Stein added. For patients who receive outpatient stroke treatment, it's important to have a physician who serves as "a central command center for a caregiving team to make sure that referrals go to physical therapy, occupational therapy, speech therapy, psychology, psychiatry, et cetera, as appropriate," said Dr. Stein.

Above all, communication and coordination are "paramount" in achieve the best possible outcomes for people who have suffered a stroke, the study's authors concluded. Without such coordination, they added, "isolated efforts to rehabilitate the stroke survivor are unlikely to achieve their full potential."

Look for a more in-depth analysis of the stroke rehabilitation guideline in the June 9 issue of Neurology Today.

The US Food and Drug Administration (FDA) has approved pimavanserin, a non-dopaminergic atypical antipsychotic, to treat symptoms of psychosis associated with Parkinson's disease, according to an April 29 announcement.

Parkinson's disease-associated psychosis, which includes hallucinations and delusions, can occur in as many as 50 percent of patients with Parkinson's disease at some time during the course of their illness, according to the FDA.

Pimavanserin is a selective serotonin 5-HT2a inverse agonist. The drug exerts its effects by blocking serotonin 5-HT2A receptors in the neocortex that are associated with symptoms of Parkinson's disease, including visual hallucinations and delusions.

In its approval notice, the FDA cited the results from the six-week, randomized, double-blind, placebo-controlled phase 3 trial that enrolled 199 adults with Parkinson's disease. Among findings, the study found Parkinson's patients showed significantly fewer features of psychosis — hallucinations, delusions, and behavior changes — compared to those taking a placebo, as measured by the Scale for the Assessment of Positive Symptoms adapted for Parkinson's disease (SAPS-PD).

In addition, the drug did not worsen the primary motor symptoms of Parkinson's disease and did not cause significant adverse effects. The most common adverse events recorded in patients were urinary tract infections (12 percent in the placebo group compared to 14 percent in the pimavanserin group) and falls (9 percent in the placebo group compared to 11 percent in the pimavanserin group). Ten recipients of pimavanserin discontinued participation in the study due to an adverse events, while two people taking the placebo dropped out. [Read the Neurology Today article about the phase 3 trial here.]

In an accompanying editorial in the Lancet, Susan Fox, MB ChB, associate professor of neurology at the University of Toronto in Canada, commented that "further studies will be needed to determine relative efficacy of pimavanserin and clozapine or quetiapine." However, she noted that the study "opens up a new therapeutic avenue in treatment of Parkinson's disease psychosis," and that pimavanserin "might help prevent progression to more bothersome symptoms" in patients with Parkinson's disease.

Patients who had a transient ischemic attack (TIA) or minor stroke and were treated at a clinic specializing in TIA were less likely to have a recurrent stroke one year later compared to historical cohorts, according to a study published in the April 21 issue of the New England Journal of Medicine. The lower risk may be explained by better and faster implementation of secondary stroke prevention strategies in contemporary TIA clinics, said the study's authors.

The researchers analyzed data on 4,789 patients in TIAregistry.org, a patient registry encompassing 61 specialized stroke care sites in 21 countries. Enrollees had experienced a TIA or a minor stroke within the previous seven days and were treated at sites with a "dedicated system for the care of patients with TIA" and "a yearly volume of at least 100 patients during the previous 3 years." Follow-up occurred at one, three, and 12 months after the qualifying event and every 12 months thereafter for 5 years, at which points patients were evaluated for "clinical events, medical treatment, and main risk factors" for stroke, including blood pressure and a lipid profile.

Researchers found that at one year after TIA or minor stroke, a total of 274 primary outcomes (major fatal or nonfatal cardiovascular outcomes) had occurred, corresponding to an event rate of 6.2 percent, and that the overall estimate of the risk of stroke was 5.1 percent. The risk of recurrent stroke was 1.5 percent at two days, 2.1 percent at seven days, and 3.7 percent at 90 days after symptom onset. These risks, noted the study's authors, were "less than half" of those observed in historical cohorts. For example, the risk of stroke and other vascular events at 90 days in the historical cohorts was 12 to 20 percent, as compared with 3.7 percent in the TIAregistry group.

The findings also confirmed that three variables were "independently associated with one-year stroke risk": a patient's ABCD2 score, which factors age, blood pressure, clinical findings, duration of symptoms, and presence or absence of diabetes; brain imaging; and status of large-artery atherosclerosis. Patients with an ABCD2 score of 6 or 7, who showed multiple infarctions on brain imaging, or who had large-artery atherosclerosis each had "more than a doubling in the risk of stroke."

The results, say the study's authors, show that prompt and targeted treatment of TIA and minor stroke in specialized TIA clinics or dedicated stroke care delivery units is associated with a reduced risk of recurrent stroke. The findings may be explained by "better and faster" implementation of secondary stroke prevention strategies at specialized stroke clinics, including "immediate initiation of antiplatelet drugs, oral anticoagulation in the event of atrial fibrillation, urgent revascularization inpatients with critical carotid stenosis, and other secondary prevention measures such as treatment with statins and blood-pressure–lowering drugs."

Furthermore, the study's authors noted that registered patients showed "good adherence to treatment recommendations," suggesting that "the risk observed during the follow-up was the risk that remained after treatment of risk factors."

The authors noted several limitations of the study, including that sites were chosen "on the basis of the existence of a TIA clinic or dedicated care for patients with TIA." The study was also biased "toward more specialized stroke physicians." However, the study's authors refute the notion that their study cohort was simply healthier than historical cohorts: "More than two thirds of the cohort had an ABCD2 score of 4 or more, and the risk that we obscured was low in each stratum of the ABCD2 score."

In an accompanying editorial, Ralph L. Sacco, MD, FAAN, chairman of neurology, and Tatjana Rundek, MD, PhD, professor of neurology, epidemiology, and public health, both at the University of Miami, noted additional study limitations. They noted that the study was "not a randomized trial" and "there was no comparison group to assess whether specialized units performed better than nonspecialized units."

However, the editorial authors said the results were "striking" and showed that "urgent care for patients with a TIA or minor stroke in specialized TIA clinics or dedicated care delivery units with stroke specialists undoubtedly works." As a result, they concluded, the study should "prompt health care providers and policymakers" to "deliver the most effective care not only to patients with acute stroke, but also to those with a TIA or minor stroke."

Look for more discussion about the study in the May 19 issue of Neurology Today.

In a case-control longitudinal study, investigators at the Johns Hopkins University reported that patients with small fiber neuropathy (SFN), irrespective of cause, experienced progressive axon loss during two to three years of follow-up, with many developing large fiber dysfunction.

Moreover, they found that SFN, which is associated with painful attacks that begin in the hands and legs, causes damage along the entire length of sensory nerve fibers, rather than just at the longest ends of the fiber first.

The findings, which were published in the April 11 online edition of JAMA Neurology, challenge the conventional thinking about SFN pathogenesis, which posits that the longest nerves degrade first.

In order to measure the natural course of SFN, the researchers tested and monitored 62 people, including 52 people with predominant SFN and 10 healthy controls, over the course of three years. Of those with SFN, 25 people had idiopathic SFN, 13 people had prediabetes or impaired glucose tolerance-associated SFN, and 14 people had diabetes-related SFN. Researchers took biopsies of patients' skin from three locations – the distal leg, the distal thigh, and the proximal thigh – at a baseline visit and at a follow-up appointment three years later.

Among their results, they observed that intraepidermal nerve fiber density (IENFD) "decreased over time in all patients at a similar rate" and that the "decrease in IENFD was similar across the three sites in all three groups of patients." The mean yearly rates of IENFD change over time at the distal leg, distal thigh, and proximal thigh were –1.42, –1.59, and –2.8 fibers per millimeter, respectively, which the study's authors say "indicate comparable rates of decrease across biopsy sites."

In addition, the data suggest that SFN is most damaging to people with diabetes and prediabetes compared with people who have idiopathic SFN. Nerve fiber density was "lower in all sites at baseline in patients with [diabetes and prediabetes] compared with [patients with idiopathic neuropathy]," the researchers reported, noting that people with diabetes and prediabetes who had SFN are "more likely to develop large fiber involvement" than those with idiopathic SFN.

"[Small fiber neuropathy] signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people's quality of life," said the study's lead author, Michael Polydefkis, MD, FAAN, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab, in a news release about the study. "The results of this new study add urgency to the need for more screening of those with [prediabetes] and faster intervention."

In an accompanying editorial, John T. Kissel, MD, FAAN, chair of the department of neurology at The Ohio State University Wexner Medical Center, and Gordon Smith, MD, FAAN, professor of neurology at the University of Utah, wrote that the study had several strengths, including an "impressive" duration of material collection — 8 years — and the inclusion of a comparison group of healthy control participants who showed no decrease in IENFD.

However, they noted that the study had a number of important limitations. Among them, they cited the small sample size and "the fact that the data were collected at a single major peripheral nerve center." They also pointed out that the IENFD values measured were "surprisingly high," which could indicate that the study population "had greater disease severity, was uniquely vulnerable to progression, or that there was some unrecognized bias in the sample." These weaknesses, according to the authors of the editorial, challenge "the central conclusion that SFN may not be length dependent."​​

People as young as 40 can show signs of arterial stiffening that can be an early indicator of cognitive decline, Alzheimer's disease, and stroke, according to a new study published online on March 10 ahead of the April 4 print edition of Stroke: Journal of the American Heart Association.

Researchers at the University of California, Davis School of Medicine culled data from 1,903 adults who participated in the Framingham Heart Study (FHS), a longitudinal study designed to identify risk factors for cardiovascular and cerebrovascular diseases. The adults studied were generally young, with an average age of 46.2 years, and healthy; they were "less likely to smoke, to receive treatment for hypertension, or have diabetes" compared to the rest of the adults in the FHS, according to the study's authors.

In order to assess the relationship between stiffening of the arteries and brain health, researchers measured various pulses and pressures in the arteries (via tonometry) and examined brain MRI on patients in the study cohort. They found that increased carotid-femoral pulse wave velocity (CFPWV), which measures the force of arterial blood flow and is "the standard noninvasive measure of aortic stiffness," was associated with injury to the brain's white matter and atrophy of gray matter. In fact, researchers found that these measures of brain health "worsened continuously with increasing" arterial stiffness. The results were accentuated in patients that were older, the study's authors said.

"This study shows for the first time that increasing arterial stiffness is detrimental to the brain, and that increasing stiffness and brain injury begin in early middle life, before we commonly think of prevalent diseases such as atherosclerosis, coronary artery disease or stroke having an impact," said the study's lead author Pauline Maillard, PhD, a researcher in the UC, Davis department of neurology and Center for Neuroscience, in a news release about the study. "These results may be a new avenue of treatment to sustain brain health," she said.

The study also noted that elevated arterial stiffness is the earliest manifestation of systolic hypertension. "Measures of arterial stiffness may actually be a better measure of vascular health, and should be identified, treated and monitored throughout the lifespan," Dr. Maillard said.​

Damage to the integrity of both gray and white matter has been tied to an increased risk of cognitive decline and Alzheimer's disease in other studies of the FHS cohort, the study's authors noted. Additionally, an increase in arterial stiffness has been associated with an elevated risk of cardiovascular injury and microvascular brain injury, including stroke. The reason, the study's authors hypothesized, may be that arterial stiffness exposes brain vessels to fluctuations in blood pressure and pulse, which "may impact supply of oxygen and nutrients to the brain."

The good news? Current treatments for hypertension may help reduce the risk. The study's authors noted that "treated hypertension is associated with more normal" brain pulse values, suggesting that "early life treatment of hypertension may be substantially more beneficial" than late life treatment for hypertensive adults.

The study's authors noted that arterial stiffness, which is associated with an increased risk of hypertension, is "easily measurable" by physicians through the same tonometric methods used in the study. Doctors should therefore consider measuring arterial stiffness in patients who are at the "greatest risk of hypertension progression" so that they may begin treatment as early as possible, the study authors concluded.​

Rosacea, a common, inflammatory skin disorder characterized by facial flushing, erythema, edema, and other symptoms, may be associated with a two-fold increased risk in the incidence of Parkinson's disease (PD), according to the results of a 15-year study published in the March 21 online edition of JAMA Neurology.

In order to assess the link between Parkinson's and rosacea, the researchers, led by Alexander Egeberg, MD, PhD, of the University of Copenhagen, followed a cohort of approximately 5.4 million Danish adults between 1997 and 2011. The study cohort excluded adults with prevalent PD or rosacea, or who were taking anti-Parkinson's agents. At the end of the study, the adults were divided into two populations: a reference population, consisting of adults who never developed rosacea, and a group of rosacea patients. Researchers surveyed inpatient and outpatient hospital records as well as prescription records in order to determine the diagnosis and treatment of both Parkinson's disease and rosacea for patients in the rosacea group.

Among findings, the PD incidence rate (per 10,000 person-years) in those with rosacea was 7.62 (95% CI, 6.78-8.57) compared with 3.54 (95% CI, 3.49-3.59) in the reference population. The disease was diagnosed an average of 2.4 years earlier in patients with rosacea than in the reference group. Moreover, the researchers reported that treatment with tetracycline in moderate to severe rosacea was associated with a reduced risk of PD.

These results may indicate a "neuroprotective effect" provided by treatment with tetracylines, the researchers wrote. But they noted that that their findings were "hypothesis generating," and further research involving randomized drug trials would be needed to corroborate the study results.

In an accompanying editorial, Thomas S. Wingo, MD, of Emory University, wrote that one study limitation was that individuals with "rosacea had increased exposure to medical professionals, potentially prompting earlier recognition of PD." But, he noted, dermatologists and general practitioners are usually not focused on neurologic illnesses.

Parkinson's disease has long been associated with neuroinflammation and other skin conditions, including seborrheic dermatitis and hyperhidrosis. Recent studies demonstrate a higher-than-average incidence of rosacea among Parkinson's patients; in one German study cited by researchers, "rosacea was present in 18.6% of participants" with Parkinson's disease.

Additionally, research has linked the increased expression of a common genetic culprit, metalliproteinases (MMPs), to both Parkinson's and rosacea. However, the study authors emphasized that "the basis for the pathogenic link between rosacea and Parkinson's disease is unknown."

Still, researchers determined that the link between rosacea and Parkinson's is strong enough that doctors may consider "rosacea or rosacea-associated features, such as facial flushing" to "support a Parkinson disease diagnosis at an early phase of the disease."

In a case-control study based in French Polynesia, researchers provided the strongest evidence yet linking the fast-growing outbreak of Zika virus infections to a concurrent, albeit much smaller, outbreak of Guillain-Barré syndrome (GBS) that occurred between October 2013 and April 2014.

Published in the February 29 online edition of The Lancet, the study found that 41 of 42 patients diagnosed with GBS in Tahiti had anti-Zika virus immunoglobulin M (IgM) or IgG, and all had neutralizing antibodies against Zika virus compared with 54 (56 percent) of 98 people in an age-matched control group (p<0.0001) admitted to the hospital with a non-febrile illness.

Neuroepidemiologists and neuroinfectious specialists who were not involved with the study praised the research, and said it added the best evidence to date of a potential link between GBS and Zika. But they agreed that it nonetheless lacked decisive proof of whether and how the virus might cause GBS. Indeed, some questioned whether the diagnosis of GBS in these cases was appropriate.

"It’s not classical Guillain-Barré syndrome. I'm not 100 percent sure what it actually is," Avindra Nath, MD, FAAN, chief of the section of infections of the nervous system and clinical director of the National Institute of Neurological Disorders and Stroke, told Neurology Today in a telephone interview from Liberia, where he was following up cases of Ebola infection that occurred last year. “They didn't find antibodies to the myelin lipids, which one would normally see in GBS,” said Dr. Nath, who was not involved with the current study. “They found it affected the axon, not the myelin. So these differences tell me it's an acute motor axonal neuropathy. It could still be caused by the Zika virus, but it may have nothing to do with the immune system."

As researchers around the world scrambled to answer such questions, the director-general of the World Health Organization (WHO) emphasized in a news conference on March 8 that public health responses cannot await definite proof of mechanisms. "We can expect to see more cases and further geographical spread," said Margaret Chan, MD.

Mosquito-borne transmission of the Zika virus, she noted, had been detected in 31 countries and territories in Latin America and the Caribbean [at press time], including three territories of the United States: Puerto Rico, American Samoa, and the US Virgin Islands.

Nine of those countries have reported an increased incidence of GBS or confirmation of Zika infection among GBS cases, she said, including Colombia and Venezuela.

"GBS has been detected in children and adolescents but is more common in older adults and slightly more common in men," Dr. Chan said. "The anticipated need for expanded intensive care adds a further burden on health systems. Reports and investigations from several countries strongly suggest that sexual transmission of the virus is more common than previously assumed. All of this news is alarming."

STUDY DETAILS AND COMMENTARY

Frédéric Ghawché, MD, a neurologist at the Centre Hospitalier de Polynésie Française in Papeete, Tahiti, and colleagues reported in The Lancet study that 93 percent (39) of the patients with GBS had Zika virus IgM, and that 88 percent (37) had experienced a transient illness in a median of six days before the onset of neurological symptoms. That suggested a recent Zika infection, the team of two dozen researchers from France, Tahiti, and Scotland concluded.

Electrophysiological findings were compatible with the acute motor axonal neuropathy (AMAN) type of GBS, the team reported, and had an unusually rapid evolution of disease, with a median duration of the installation and plateau phases of six and four days, respectively.

The researchers detected anti-glycolipid antibody activity in 31 percent (13) of the patients, and notably against glycolipid GA1 in eight (19 percent) patients by ELISA and 19 (46 percent) by glycoarray at admission.

As Dr. Nath noted, the researchers found that the typical AMAN-associated anti-ganglioside antibodies were rarely present. Past dengue virus history did not differ significantly between patients with GBS and those in control groups.

Despite the uncertainties, Dr. Nath called the study the most convincing evidence to date linking Zika infection to a GBS-like condition.

"The researchers did take considerable efforts to ensure that the serological reactions they observed were directed toward Zika and not just cross-reacting with dengue," he said. "The results are pretty impressive from an epidemiologic as well as laboratory standpoint. Having said that, it's not quite a slam dunk. It's one study. One would like to see the results replicated."

A commentary accompanying the paper in The Lancet noted the same unusual presentation of the cases in Tahiti as Dr. Nath observed. "The researchers did not find the expected pattern of antibodies, nor did they find evidence for molecular mimicry between Zika virus antigens and the anti-glycolipid antibodies that might induce an autoimmune response," wrote David W. Smith, MD, a pathologist at the University of Western Australia, and John Mackenzie, PhD, a professor of tropical diseases at Curtin University in Australia.

"Flavivirus antibodies are widely cross-reactive across the species," the commentary stated, "and there are also cross-species immune recall phenomena that can lead to spurious early antibody responses when the person has had another flavivirus infection in the past. In fact, only one of the 42 cases showed the standard criterion of neutralization titres to Zika virus that are four-fold or higher than the titre to the dengue viruses."

Even so, the commentary concluded that it is "very likely" that most of the patients had recently been infected with Zika. "Suffice it to say Zika virus can be added to our list of viruses that can cause Guillain-Barré syndrome," Dr. Smith and Dr. Mackenzie wrote.

But Daniel M. Pastula, MD, MHS, a neurologist and medical epidemiologist at the University of Colorado Anschutz Medical Campus in Denver, who also was not involved with the study, questioned the diagnosis of GBS in these cases. He noted that the study failed to use recently developed criteria for diagnosing GBS by the Brighton Collaboration, an independent global vaccine safety safety research network for health care professionals.

"The Brighton Collaboration criteria is now used across epidemiologic studies for GBS," Dr. Pastula said. "This paper would have been more robust if they had used the criteria."

TREAMENT OUTCOMES

All 42 of the GBS patients in the Tahiti case-control study received the standard therapy for the disorder, intravenous immunoglobulin, and one also underwent plasmapheresis. The median duration of hospital stay was 11 days (with a range of seven to 20) for all patients, and 51 days (with a range of 16 to 70) for the 16 patients who were admitted into intensive care. Three months after discharge, 24 of the patients (57 percent) were able to walk without assistance.

Those outcomes, while within historical norms and reassuring to the majority of patients, nevertheless demonstrate that the illness is not self-limiting for all patients, said Dr. Pastula.

"Previous data suggests about 85 percent of people are walking independently at one year," he said. "But others may not fully recover. At one year, full recovery of motor strength occurs in about 60 to 70 percent of patients. Severe motor problems persist in about 15 percent."

Because it remains unclear whether the neurologic effects observed in Tahiti are due to an immune reaction to the virus or a direct injury by the virus itself, Dr. Nath questioned whether immune therapies make sense.

"Currently the recommendation is to treat with immune therapies," he said. "I'm not sure that will do anything. We need to do clinical trials. We may be doing the wrong thing."

Even so, immune therapies would be unlikely to have any ill effect on the AMAN subtype of GBS, said Kenneth L. Tyler, MD, FAAN, professor and chair of neurology at the University of Colorado Anschutz Medical Campus in Denver.

"We have no reason to believe that IVIG, which we normally use to treat Guillain-Barré, would have any harmful effect in these cases," Dr. Tyler said. "Whether they would have a beneficial effect, I don't know. But I'm not aware of any data that would suggest that the usual therapies would be harmful. The outcomes for the patients in Tahiti were not bad based on this preliminary data."

WHAT TO EXPECT

“In 2015, Brazil most definitely had a Zika outbreak and an accompanying increase in GBS cases," said James J. Sejvar, MD, a neuroepidemiologist in the Division of High-Consequence Pathogens and Pathology at the CDC's National Center for Emerging and Zoonotic Diseases in Atlanta.

"We haven't heard of any increased reporting of either Zika or GBS in Brazil this year yet. If Zika is going to recur there, we're only now getting into the period where we should start to see it. The rainy season has now ended; that's when the mosquito larvae start to hatch. We would expect the peak of Zika cases to be around March, April, May."

The CDC, he noted, already has a team there prepared to run a case-control study of GBS cases should they recur.

In a report on its website, the WHO noted that Colombia typically registers about five cases of GBS per week, but saw 86 GBS in a recent five-week period, three times higher than average. During the month of January, Venezuela recorded 252 GBS cases with a spatiotemporal association to Zika virus.

J. David Beckham, MD, an associate professor of medicine in the divisions of infectious diseases, neurology, and immunology & microbiology at University of Colorado-Denver, told Neurology Today that he is working with the CDC to analyze serum samples from patients in Colombia.

"They'll be sending us blood from these patients who are acutely infected so we can look at T-cell responses and antibody responses," he said.

As for the United States, Zika transmission has already begun, said Dr. Sejvar. "There's definitely Zika transmission in Puerto Rico," he said. "We've set up active surveillance for GBS in Puerto Rico in anticipation that they may experience an outbreak of GBS."

For the continental United States, it is likely only a matter of months until Zika infections are seen in Florida and the Gulf states, said Dr. Nath.

"We're very worried that the southern parts of the United States," he said. "The CDC is already monitoring the mosquito population in Florida and elsewhere."

Whatever the number of Zika infections might turn out to be in the United States, any associated cases of GBS are certain to be far fewer, according to epidemiologic evidence. A study published in 2013 in Lancet Neurology calculated a GBS rate of 0.24 per 1,000 Zika virus infections, or about one case for every 4,000 infections.

"Be watchful and be observant for unexpected clusters of Guillain-Barré syndrome, either in its conventional form or, based on this paper, in its ANAM form," Dr. Tyler said. "If you begin to see a higher than expected incidence of this disease, which in most settings is sporadic, then that would be of concern."

Treating insulin resistance with pioglitazone following an ischemic stroke or transient ischemic attack (TIA) appeared to prevent another stroke or myocardial infarction (MI), according to results from a five-year multicenter study.

The non-diabetic patients enrolled in the Insulin Resistance Intervention after Stroke (IRIS) trial screened positive for insulin resistance using a simple fasting blood test that is not yet part of the routine post-stroke workup.

IRIS study investigators enrolled 3,876 non-diabetic patients from 167 centers in seven countries and randomized them to receive either pioglitazone or a placebo for almost five years. At the end of the study, they found that the diabetes drug reduced the absolute risk of recurrent stroke and heart attack by 2.8 percent and the relative risk by 24 percent.

This relative risk reduction is comparable to or possibly greater than that reported for either aspirin or statin therapy, said Walter N. Kernan, MD, a professor of general medicine at Yale School of Medicine and first author of the NEJM study.

The active treatment also cut in half the risk of diabetes, and it reduced blood sugar, systemic inflammation, triglyceride levels, and systolic blood pressure. It favorably increased the concentration of high-density lipoprotein (HDL) cholesterol but also increased low-density lipoprotein (LDL) cholesterol in study subjects receiving pioglitazone.

"This is the first study to show that pioglitazone could have vascular benefits in a non-diabetic population," Dr. Kernan said. "The treatment of insulin resistance offers a potentially new preventive strategy to help reduce the risk for recurrent stroke or heart attack."​

The National Institute of Neurological Disorders and Stroke, which funded this prevention study, appointed an independent data and safety monitoring board to conduct interim analyses. The study investigators screened more than 7,500 people older than 40 years who had had a recent ischemic stroke or TIA. Anyone with a history of diabetes or a glycated hemoglobin level over 7.0 was excluded from the study. (There were other exclusion criteria that can be found in the methods section of the study.)

Study participants had to have insulin resistance that was defined "as a value of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index." The index threshold of 3.0 was chosen because it identifies the highest quartile among populations without diabetes, the researchers wrote. And because insulin sensitivity may be transiently impaired after a stroke, the screening blood test was conducted at least 14 days after the index event.

The researchers enrolled 3,876 non-diabetic patients with insulin resistance and randomly assigned half to receive pioglitazone and the others to a matching placebo pill. Pioglitazone was titrated from an initial dose of 15 mg to a final dose of 45 mg. Study participants remained on that dose for the remainder of the five-year study. (The researchers reported that 60 percent were still taking the study drug at the end of the study.)

At the end of the study, 175 of the 1,939 patients (9.0 percent) in the pioglitazone group and 228 of 1,937 (11.8 percent) of those who had been taking a placebo pill had had a stroke or MI (p=0.007). There were also other significant changes in secondary outcomes: the rate of progression to diabetes was 3.8 percent in the pioglitazone group compared with 7.7 percent in the controls (p<0.001). People taking the active medication also had lower levels of fasting glucose, fasting triglycerides, systolic blood pressure, and higher levels of HDL.

These benefits must be weighed against the adverse events reported in the study, the IRIS researchers noted. People in the pioglitazone group had more weight gain (52 percent gained 4.5 kg compared with 33.7 percent in the controls, and 11.4 percent gained more than 13.6 kg compared with 4.5 percent of those taking a placebo); edema (35.6 percent versus 24.9 percent for the active drug and placebo, respectively); and bone fractures requiring hospitalization or surgery (5.1 percent versus 3.2 percent, respectively). LDL cholesterol levels were also increased in those patients taking pioglitazone.

Pioglitazone did not lead to an increase in heart failure. Previous observational studies reported a signal of increased bladder cancer among patients taking pioglitazone, but this study showed no statistically significant differences in rates of bladder cancer between those on the medicine and those taking a placebo.

The results suggest that treating 100 patients with pioglitazone for five years will prevent three from having a recurrent stroke or heart attack. That said, two in every 100 patients on the active medicine would have been expected to suffer a bone fracture serious enough for surgery or hospitalization during that same five-year period.

"The IRIS trial puts insulin resistance on the map. This is the first trial to show, in its primary aim, that a diabetes drug targeting insulin resistance can prevent stroke and heart disease," said Dr. Kernan. "The treatment effect of pioglitazone in terms of relative risk reduction is at least as large as we have seen with aspirin or statin therapy. It will still take time for the community of neurologists to consider these results and how they should incorporate them into practice."

"My hope is that the findings will invigorate research into both pioglitazone and other therapies that work on the same biological pathways as pioglitazone," he added, pointing out that insulin resistance can be measured in clinical practice using the HOMA test.

"I am not saying that everyone should use this drug," he said. "The drug will need to be prescribed with care."

Look for more independent analysis of these findings in the March 17 issue of Neurology Today.